Definitions

Acute pain is always associated with tissue damage; as tissue heals, pain should resolve. The definition of acute pain in the Michigan health code focuses on the cause and limited duration: “pain that is the normal, predicted physiological response to a noxious chemical, or a thermal or mechanical stimulus, and is typically associated with invasive procedures, trauma, and disease and usually lasts for a limited amount of time.” The International Association for the Study of Pain (IASP) further emphasizes the time limit for acute pain: it is pain lasting less than 3 months.

Subacute pain is a subset of acute pain: pain that has been present for at least 6 weeks but less than 3 months. This definition reflects the process of tissue healing. The worst of the acute pain phase and inflammation is no longer present, but ongoing tissue healing is required for full resolution.

Chronic pain has little in common with acute pain and should be considered as a separate medical condition. Some differences are:

The differing pathophysiology for acute pain and chronic pain requires different approaches to their diagnosis and treatment. Effective acute pain management has been shown to improve both patient satisfaction and treatment outcomes, and reduce the risk of developing chronic pain.

Diagnosis and Treatment

Diagnosis. Identify the medical or surgical condition for which acute pain is a symptom (see Table 1). Often the cause is obvious or revealed by the history. If the diagnosis is not immediately clear, history, physical examination, laboratory tests, and imaging may all be employed to arrive at the diagnosis.

Table 1

Acute Pain Overview by Severity and Cause.

Determine whether this is acute nociceptive pain (signaled to the brain via normally functioning afferent neural pathways) or acute neuropathic pain (dysfunctional neural functioning). Nociceptive and neuropathic pain are described in more detail below, under “General Approach to Chronic Pain”. This classification helps guide the treatment plan and medications to prescribe.

In some cases, the cause is not immediately obvious, but the category of pain is. For example, burning pain starting in the neck and radiating into the fingers could be associated with acute cervical radiculopathy or may evolve to reveal zoster. Both are types of acute neuropathic pain. Strategies would include reducing inflammation, quieting of nerves. and further diagnostic work up to determine the exact cause. Weakness may point towards radiculopathy, while the presence of a rash points towards zoster.

Assess the degree of functional impairment to help determine the urgency for addressing the acute pain issue. For example, weakness may require a more aggressive strategy with early intervention, such as advanced imaging. If a patient is no longer able to carry on a usual routine or activities of daily living due to acute pain, an aggressive diagnostic workup is needed. An aggressive workup is also required in patients with a history of malignancy or immunosuppression.

Treatment. In the treatment plan, address both the underlying cause and the associated acute pain. In developing a treatment plan for the acute pain, consider the degree of tissue trauma, the patient’s situation, and any unique patient factors. A patient in the immediate postoperative period after a major surgery will likely have more complex needs than a patient presenting for an ambulatory encounter.

The hallmark of acute pain is tissue inflammation. Acute pain can be nociceptive or neuropathic. Accordingly, measures to reduce inflammation are helpful when developing a treatment plan for acute pain conditions. Some treatments to consider for acute pain include those listed in the table below:

Plan for treatment of reinjury or exacerbation during the subacute pain phase. Often subacute pain occurs with increase in activity before tissue is completely restored to health. Have a plan to escalate analgesic needs for this well-defined occurrence. For example, anticipate how pain with physical therapy should be treated.

Biological and Psychosocial Factors

Chronic pain – pain that lasts or recurs for longer than 3 months – is not merely acute pain that does not resolve. Increasingly, chronic pain is recognized as a disease entity in and of itself, rather than as a symptom of another disease. Historically, pain has been viewed in a biomedical model, with a focus on identifying a specific pathologic cause of pain which can be treated through pharmacologic or interventional means. However, chronic pain is better understood by applying a biopsychosocial model. Chronic pain is a complex multi-dimensional condition, driven by the interplay of neurobiologic processes with psychosocial factors that may increase vulnerability or resilience to disease.¹⁶ A biopsychosocial approach allows the focus to move from the source of the pain to the management of its impact.

Neural mechanisms of Pain. Understanding the basic neurobiological mechanisms in chronic pain pathophysiology is important, since treatment approaches vary depending on these factors. There are three main subtypes of pain pathophysiology: nociceptive, neuropathic, and central sensitization. They are summarized below, with more detail regarding classification in Table 2.

Nociceptive pain is caused by tissue damage due to injury or inflammation, rather than harm to the central or peripheral nervous system. This is the primary type of pain involved in patients with arthritis, musculoskeletal inflammatory disorders (tendinosis, bursitis), or structural spine pain.

Neuropathic pain results from damage to the sensory nervous system. Patients typically describe electric, burning, or tingling sensations. Examples of neuropathic pain include post-herpetic neuralgia, diabetic neuropathy, and trigeminal neuralgia.

Central sensitization occurs when there is heightened pain sensitivity in the central nervous system that is not due to a peripheral pain signal generated by an injury or disease state. Central pain is driven by molecular and structural changes that occur in the central nervous system. It is the primary mechanism in conditions such as fibromyalgia, phantom limb syndrome, and chronic pelvic pain.

Psychosocial factors. Chronic pain has significant cognitive, affective and interpersonal components. Patients with chronic pain are more likely to report depression, anxiety, poor quality of life, and financial stress. They are five times more likely to use health care resources than patients without chronic pain. Pain beliefs and the individual and family response to chronic pain are also important factors.

Chronic Primary and Secondary Pain Syndromes

A classification system for chronic pain syndromes has been devised by the International Association for the Study of Pain (IASP), as outlined in Table 2.

Chronic primary pain syndromes. These syndromes represent a disease itself. A chronic primary pain syndrome is defined as pain in one or more anatomical regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or functional disability (interference with activities of daily life and participation in social roles) and that cannot be better accounted for by another chronic pain condition.¹⁷

Chronic primary pain syndromes include:

• Fibromyalgia
• Complex regional pain syndrome
• Chronic primary headache and orofacial pain
• Chronic primary visceral pain
• Chronic primary musculoskeletal pain

Chronic secondary pain syndromes

Each of these syndromes initially manifests as a symptom of another disease. After healing or successful treatment, chronic pain may sometimes continue and hence the chronic secondary pain diagnoses may remain and continue to guide treatment (Table 2).¹⁵

Chronic secondary pain syndromes include:

• Cancer-related pain (eg, from tumor mass or treatment)
• Chronic postsurgical or posttraumatic pain
• Chronic neuropathic pain
• Chronic secondary headache or orofacial pain
• Chronic secondary visceral pain
• Chronic secondary musculoskeletal pain

Establishing the diagnosis of a specific chronic pain syndrome can be an important first step in providing clarity for the care team, psychoeducation for patients, and direction for treatment considerations. In order to arrive at a diagnosis, perform a thorough biopsychosocial assessment.

Pain Characteristics

Determine the location, quality, intensity, and time course of the pain. Pain intensity scales have a limited role in chronic pain.

Pain location. Pain drawings are frequently used for patients to identify the location of pain. A drawing on an anatomical outline can provide a quick impression of the breadth and character of the presenting pain complaint. However, quantitative ratings of pain drawings are not consistently associated other aspects of pain disability. Therefore, pain drawings are not adequate to form clinical conclusions (eg, contribution of psychological causation for pain and disability).

Pain quality. A detailed account of pain quality may help identify potential types/sources of pain. Musculoskeletal or myofascial pain is often described as aching, throbbing or tight. Primarily neuropathic pain can be described as shooting, burning, or electric. Visceral pain may be gnawing, deep, and difficult to localize. Many patients will report more than one type of pain, but pain quality assessment will help guide treatment.

Pain intensity. A patient’s report of pain intensity provides a subjective gauge of the distraction and interference pain causes in their daily life.

While pain intensity scales are useful in assessing and treating acute pain, they have a limited role in assessing and treating chronic pain. While chronic pain intensity is important to assess, ten-point pain scales that assess only pain severity or intensity (including various single-item written or visual scales) do not adequately assess broader functional effects of chronic pain. See below for pain scales that address the functional impact of pain and level of acceptance of pain.

Complete analgesia, which means achieving a pain assessment score of zero, is not possible for most patients with chronic pain. Use the intensity score in conjunction with the functional assessment to set treatment goals and monitor treatment effectiveness. Analgesia without improved function is not a legitimate treatment goal.

Patients should understand that reducing pain intensity will not be the sole focus of evaluation or management. This requires a shift in expectations for many patients accustomed to an acute pain management model.

Pain time course. Evaluate changes in pain location, quality, and severity through time. Reassess changes at regular intervals and modify treatments as appropriate.

Pain Treatment History

Many patients with chronic pain have long and sometimes complex treatment histories. Obtain a full history, including:

• Details of treatment success or failure. Ask: “What has worked best to manage your pain?” “What has not worked?”
• Review medication list prior to visit. If medication was trialed previously, why was it stopped? Was there an intolerance? At what dose was each drug tried before labeling as “ineffective”? How long was each drug taken?
• Relevant surgeries, other procedures, and hospitalizations, particularly for pain control
• Perceived origin of pain (work injury, car accident, trauma) and any associated disability or legal actions
• Personal or family history of psychiatric problems, substance misuse, substance use disorder, or other significant medical problems.

Verify these details by reviewing internal records, obtaining outside documentation, and contacting other treating clinicians as necessary.

Quality of Life and Functional Impact

Objective assessment of a patient’s function is essential in managing chronic pain. Tools are available to establish functional impact at baseline and progress on functional impact through treatment. For example, the 3-item PEG Scale¹⁸ (Appendix A2) assesses Pain intensity, Enjoyment of life, and interference with General activity. This tool is useful to track an individual’s function as it changes over time. Therapy should result in the individual’s score decreasing. Scores are not directly comparable between patients because individuals vary on which aspect (pain, enjoyment, general activities) is most important.

Comorbid Conditions

The presence of comorbid conditions often impacts treatment decisions.

Medical comorbidities. Obtain a thorough past medical history, with attention to conditions that may raise the risk for harm with pain treatment. Conditions that merit special considerations in pain treatment include sleep disordered breathing, chronic kidney disease, liver disease, cardiopulmonary disease, and neurologic disorders.

For example, obstructive sleep apnea, and other forms of sleep-disordered breathing raise the risk for adverse outcomes and overdose with opioids. Opioids increase the likelihood of central sleep apnea and to a lesser extent obstructive sleep apnea.¹⁹ These effects are compounded when a patient already has sleep-disordered breathing at baseline.

Psychiatric comorbidities. Review the past medical history and assess the presence of psychiatric conditions that could affect the patient’s response to chronic pain, communications with the patient about chronic pain, or treatment.

A primary psychiatric condition may contribute to the worsening of chronic pain. Also, psychiatric conditions may develop secondary to chronic pain.

Depression and anxiety disorders are four times more likely among patients with chronic pain than pain-free patients.²⁰ Post-traumatic stress disorder (PTSD) is another common comorbidity.²¹ It is a risk factor for chronic pain^22,23 and for the transition from acute to chronic pain.²⁴ PTSD in abuse survivors has been linked to increased severity of pain and disability.^25,26

Psychiatric comorbidities may affect treatment and referral. Clinicians should be familiar with standard guidelines regarding management of these conditions. (For example, see Michigan Medicine Depression Guideline). Initial treatment for psychiatric disorders in patients with chronic pain may be influenced by their specific pain syndrome (see non-opioid pharmacologic treatment). If patients do not have an adequate response to therapy, refer them for specialty evaluation, which may involve pain psychology.

Substance use disorders. Obtain a substance use history in all patients with chronic pain, including the use of alcohol, illicit drugs, tobacco, and caffeine. When the etiology of pain is unclear, this history can help assess the risk for substance use disorder prior to considering treatment with opioids. Obtain a family history of substance use disorders as part of a comprehensive risk assessment. Consider use of a standardized screening tool, such as the drug abuse screening test (DAST-10) or the Michigan opioid risk assessment (MORA). It is important to document substance use disorders accurately and specify if the substance use is active or in remission, Avoid stigmatizing labels in documentation such as “drug-seeking” or “addict”. Instead, use DSM-V diagnostic language. Avoid copying forward progress notes that contain stigmatizing language, or inaccurate information regarding the patient’s substance use.

Suicidality. Assess patients with chronic pain for suicidality. Chronic pain is associated with an increased risk of suicidality. In a 2018 study of suicide decedents, 8.8% had evidence of chronic pain, and the percentage increased from 7.4% in 2003 to 10.2 % in 2014. More than half of suicide decedents with chronic pain died of firearm-related injury, and 16.2% died of opioid overdose. These data likely underrepresent the true number of suicide decedents with chronic pain.²⁷

Pain Beliefs and Response to Pain

Pain beliefs and responses to pain may have a positive or negative effect on treatment outcomes. For patients who exhibit negative affect, pain catastrophizing, or other negative pain-specific constructs, consider evaluation by pain psychology. The Chronic Pain Assessment Questionnaire (Appendix A3) evaluates a patient’s level of acceptance of their pain, with higher acceptance levels correlating with more successful response to chronic pain management. Self-efficacy and positive treatment expectations can increase resilience and functional outcomes.²¹ Positive cognitive and emotional coping mechanisms can be promoted through multidisciplinary treatment incorporating education, psychological therapies and mindfulness.

Several cognitive constructs and affective responses negatively influence the intensity, distress and dysfunction of the chronic pain experience. Negative affect or emotional distress may be below the threshold for diagnosis of psychiatric disorder (eg, anxiety, depression), yet still have a substantial influence on pain-related outcomes and response to treatment. Negative affect increases the likelihood of transition from acute to chronic pain and is correlated with increased levels of disability, health care costs, mortality, and suicide.²¹ Catastrophizing, where beliefs about the pain experience overwhelm the capacity to function, correlates with negative affect, but also has a unique impact on outcomes, and confers a degree of treatment-resistance.²¹ Fear of pain is closely connected, and leads to a cycle of hypervigilance and avoidance of activity that contributes to negative affect, physical deconditioning, and disability.²¹

Psychosocial Factors

Obtain a thorough social history of interpersonal relationships at home, work, or in other environments that may improve or negatively impact the adjustment to chronic pain. Consider screening patients with chronic pain for a history of trauma and for adverse childhood experiences. In one meta-analysis, individuals with a history of trauma were 2.7 times more likely to have a functional somatic syndrome such as fibromyalgia or chronic widespread pain.²⁸

A variety of psychosocial factors, including patient vulnerability and resilience, influence the development and experience of chronic pain, and affect outcomes such as pain persistence and disability. Functional MRI studies suggest that these psychosocial factors may have neurobiological and structural correlates that impact the central nervous system to either worsen or ameliorate pain.

Cognitive and affective responses may be influenced by spouses or other family members. Spirituality is often overlooked during pain assessment. For many patients, spirituality is an important factor that can influence the experience of chronic pain. Isolation, economic disparities, level of education and access to resources all merit consideration

Physical Exam and Diagnostic Testing

Perform a comprehensive physical exam in patients with chronic pain. Review imaging and other diagnostic testing (x-rays, MRI, EMG, lab studies, etc.). Review urine drug test results. Review the state prescription drug monitoring report (PDMP) report, MAPS in the state of Michigan).

Arriving at a Diagnosis

After obtaining the history, doing a physical exam, reviewing records and diagnostic test results, assign a diagnosis of chronic pain that identifies:

• The most likely neurobiologic mechanism of the pain: nociceptive, neuropathic, or central sensitization (Table 2).
• Whether it is a primary or secondary chronic pain syndrome.

In some cases, underlying neurobiologic mechanisms may be overlapping, and more than one pain syndrome may be present.

If the diagnosis is uncertain, additional workup may be necessary, including diagnostic testing or specialty consultation. However, even when the underlying pathophysiology is unclear, establish a therapeutic relationship with the patient, and begin developing an individual pain treatment plan.

Shared Decisions for Individualized Treatment

A trusting patient-clinician relationship is key to the development of an effective treatment plan for chronic pain. Construct a unique plan for each patient, taking into consideration the individual’s experience, circumstances, and preferences. The treatment plan should involve multimodal interventions, promote self-management, and enlist the involvement of a health care team. Use a shared decision-making approach, where patients and clinicians discuss values and preferences, review risks and benefits, and make a decision congruent with patient goals and preferences.²⁹ Frequently reassess and adjust the plan to address barriers to care.

Key to developing an effective treatment plan is a supportive relationship with an empathetic clinician who acknowledges and empathizes with the patient’s experience. Set expectations regarding the available treatments for chronic pain. Establish realistic treatment goals for functional improvement or maintenance, not analgesia alone. Inform the patient that finding the right approach may take time.³⁰ Facilitate patient self-management and provide pain psychoeducation (see Appendix H). A team-based approach is helpful in this effort, involving other clinical disciplines such as nursing or behavioral health consultants to provide coaching, education, and support.

A logical rationale for an intervention does not ensure the patient’s acceptance and participation in it. A patient’s acceptance of therapy is influenced by several complex factors, including characteristics of illness and identity. Patient preferences often favor physical rather than psychological intervention, but gains of psychological therapies may exceed patient expectations.³¹

Preferred Interventions

Non-pharmacologic therapy and non-opioid pharmacologic therapy are preferred for the treatment of chronic pain.¹¹ There is insufficient evidence to support the use of long-term opioid use for chronic pain. Opioids carry substantial risks of harm. Use shared decision-making to choose treatment interventions. A single intervention is unlikely to be fully effective for chronic pain, since chronic pain is a complex disease process with multiple contributing biopsychosocial factors. Combining several modalities, and emphasizing self-management is most effective.³² (Figure 1)

Clinician and Health Care System Barriers

When patients with chronic pain feel judged or scorned by health clinicians, this stigma can be a significant barrier to effective care. Similarly, clinicians caring for patients with chronic pain often experience negative emotions such as frustration, lack of appreciation, and guilt.³⁰

Patients and clinicians alike encounter frustration when confronted with barriers within the health care system. Common barriers include difficulty in accessing care, limited time for visits, and inadequate reimbursement for evidence-based treatments.

A team-based approach, adequate consultative support, and training can begin to address some of these barriers. Patients may have individual barriers to accessing care or participating in self-management. Provide them with specific support as needed.

Assess cognitive and verbal ability

For patients with cognitive and/or verbal disability, when analgesic plan involves a caregiver, caregivers should receive additional education on pain assessment. Providers should also carefully assess function and goals with both patient and caregiver.

• Assess fall risk, cognition, respiratory status, and risk for sleep disordered breathing prior to prescribing opioids.
• Reduce the initial dose of opioids by 25-50% and titrate slowly to avoid over sedation.
• Consider using a non-verbal pain scale such as CPOT (Critical Care Pain Observation Tool) or FLACC (Face, Legs, Activity, Cry, and Consolability) to assess efficacy of pain medications.
• Exercise universal precautions for controlled substance prescribing and limit pill count for patients at risk of having their medications diverted
  • - Schedule frequent follow up with patients
  • - Consider random urine drug screen (UDS)
  • - Consider pill counts
• Emphasize the importance of keeping medications secure and locked to care provider/home manager.
• Provide disposal information for unused pills
• Ensure caregiver receives education on appropriate Intranasal Narcan use and administration to the patient if indicated

Health inequity and disparity

Many patient populations are unintentionally marginalized by both health care providers and health systems. This inequity is especially true with regard to pain management amongst non-white Hispanic, black, and other minority populations.^33,34 Several factors should be considered when treating these vulnerable patients. It is the provider’s responsibility to recognize that inequity in this area is due in part, but not limited to, systemic barriers and complex influences such as implicit biases unbeknownst to providers. For example, patients with sickle cell disease frequently report difficulties in obtaining adequate pain relief from providers during a vaso-occlusive crisis. In this vulnerable population, studies have shown delays in administering pain medications due to accusations of drug seeking behavior, exaggeration of pain, and uninformed or negative attitudes held by providers concerning sickle cell disease.³⁵

To diminish these inequities surrounding pain management, providers should attempt to remove as much individual discretion from decision making as feasible. When possible, providers should utilize resources such as: checklist, guidelines, or system protocols to avoid the influences of implicit biases on their management. Providers need also recognize access limitations faced by patients and ensure any treatment regimen or follow-up planning is readily accessible. An important consideration is to involve these patients in shared decision making while offering all available treatment options to circumvent and mitigate any healthcare related obstacles these patients may encounter. Alternative options should then be explored based on individual circumstances.

Lifestyle Management

Exercise. For all patients recommend regular exercise as a component of multimodal treatment. Decrease the patients’ fear of movement. Encourage a progressive aerobic exercise program with a goal of at least 150 minutes of moderate-intensity exercise weekly. Adjust this goal for each individual’s physical status.

Exercise is structured, repetitive, physical activity to improve or maintain physical fitness. In patients with chronic pain, exercise improves both function and chronic pain symptoms, in addition to overall health and quality of life. Forms of exercise that have been studied include aerobic exercise, resistance-based exercise, water-based exercise, and styles of exercise such as yoga (for chronic primary musculoskeletal pain³⁶), tai chi (for chronic primary musculoskeletal pain, osteoarthritis, osteoporosis, neck pain³⁷), and Pilates (for chronic primary musculoskeletal pain neck pain, osteoporosis³⁸). Studies vary considerably in mode of exercise, content of program, frequency, and duration of activity. In most studies, the frequency of exercise was between 1–5 times per week, averaging 2–3 times a week. Another factor was whether activities were performed in supervised sessions or as home exercises, with home exercises potentially increasing the frequency of the activity. Prescribed exercise was generally moderate to moderately-high in intensity. No one type of exercise has been shown to be superior to another in all patient populations.

Sleep. For all patients recommend good sleep habits. Screen for sleep disturbance. Sleep complaints occur in 67–88% of individuals with chronic pain. Sleep and pain are often linked. Sleep disturbances may decrease pain thresholds and contribute to hypersensitivity of neural nociceptive pathways. Conversely, pain may disturb sleep. Nonpharmacologic sleep treatments are associated with improved fatigue and sleep quality. However, the effect on pain is comparatively modest and short-lived.

Diet. Recommend a Mediterranean pattern of eating to lower inflammation and maintain a healthy weight. Although inflammation is part of the nociceptive process, research into the role of diet in modifying inflammation is in its early stages. The Mediterranean pattern of eating, characterized by a high intake of fruits, vegetables, whole grains and an emphasis on omega-3 fatty acids, has been established as a dietary pattern that lowers inflammation especially in the setting of cardiovascular disease.³⁹ Emerging evidence shows connections between the Mediterranean pattern, lowered inflammation, and improvement in pain and function in osteoarthritis.⁴⁰

Physical Modalities

Physical therapy. If patients have functional deficits or secondary pain generators that directed therapy may improve, refer them to physical therapy.

The goal of physical therapy is to improve function. Therapeutic exercise, other modalities, manual techniques, and patient education are part of a comprehensive treatment program to accomplish this goal.

• Modalities such as hot packs, ice, ultrasound, transcutaneous electrical nerve stimulation (TENS), iontophoresis, and traction may decrease pain and increase tissue extensibility, thereby facilitating stretching and mobilization. Table 4 reviews selected modalities.
• Manual therapy helps optimize proper mobility, alignment and joint biomechanics.
• Therapeutic exercise consisting of stretching, strengthening, conditioning, and muscle re-education is useful in restoring joint range of motion, muscle strength, endurance, and to correct muscle imbalances.

Evidence is limited regarding the long-term benefit of any single individual treatment modality. However, they may be used as part of a multimodal treatment program to improve function, quality of life, and alleviate pain.

The basic components of a physical therapy prescription include:

• Diagnosis for which therapy is being prescribed.
• Therapeutic protocol for treatment, including therapeutic exercise, other modalities, and manual techniques to be employed or tried.
• Duration and frequency of desired therapy.
• Precautions.

When treatment goals have been met or when progress plateaus, formal therapy may be discontinued, but advise patients to continue with a program of independent daily home exercise.

Transcutaneous electrical nerve stimulation (TENS). Consider TENS either along with physical therapy or as an adjunct to multimodal treatment. TENS applies low voltage electrical stimulation using skin contact electrodes. Proposed mechanisms of action include gate control theory, endorphin theory, and augmentation of descending inhibition. Evidence is limited for the efficacy of TENS in pain management.⁴¹ However, it is relatively safe, with units relatively available and easy to use.

Do not use TENS near implanted or temporary stimulators (eg, pacemakers, intrathecal pumps, spinal cord stimulators), near sympathetic ganglia or the carotid sinus, near open incisions or abrasions, over thrombosis or thrombophlebitis, or in pregnancy. Use caution with patients with altered sensation, cognitive impairment, burns, malignancy, or open wounds.⁴¹

Massage therapy. Consider massage therapy as part of a multimodal treatment plan. Massage therapy is manual manipulation of muscles and connective tissue to enhance physical rehabilitation and improve relaxation. It can reduce pain scores for patients with low back pain,⁴² knee osteoarthritis,⁴³ juvenile rheumatoid arthritis,⁴³ chronic neck pain,⁴³ and fibromyalgia.⁴² Not yet determined are the optimal number, duration and frequency of massage sessions for treating pain.

Behavioral Health Approaches

Refer patients with significant psychological issues (eg, comorbid psychiatric condition; previous physical, emotional, or sexual trauma; challenges in managing and coping) to a psychologist or therapist. Consider referring any patient with chronic pain to a psychologist or therapist to address the psychological effects of chronic pain. These interventions can be successful regardless of the patient’s baseline status.

Current psychological interventions for chronic pain are based on recent advances in our understanding of the complexity of pain perception. Pain is influenced by a wide range of psychosocial factors, such as emotions, sociocultural context, and pain-related beliefs, attitudes and expectations.

Chronic pain that persists for months or years often initiates a progressive loss of control over numerous aspects of one’s psychological and behavioral function. A biopsychosocial model is now the prevailing paradigm for interventional strategies designed to treat chronic pain. This model places an emphasis on addressing cognitive-behavioral factors pertinent to the patient’s pain experience.

The strong evidence for the contribution of psychosocial factors in pain experience, particularly in explaining disability attributed to pain, has led to the development of multidisciplinary pain rehabilitation programs (MPRPs) that simultaneously address physical, psychological, and functional aspects of chronic pain disorders. For some patients, referral for individual behavioral and psychological intervention may be all that is required.

Cognitive behavioral therapy (CBT). The way patients think about themselves, others, and the future can have a major impact on their moods, behavior, and physiology. The two main tenants of CBT approaches to chronic pain are:

• The feeling of pain and the emotional, physical, and social impact of pain are interrelated, but can be separated for treatment purposes. Therefore, problems with functioning related to pain can be addressed even if pain is not targeted directly and remains unchanged.
• Psychological factors can influence the experience of pain itself.

Cognitive restructuring involves several steps that help to modify the way in which patients view pain and their ability to cope with pain. Treatment approaches that incorporate these principles can produce significant benefits, such as reduced pain, improved daily functioning, and improved quality of life.^44–48

Mindfulness-based stress reduction. Mindfulness is a process of openly attending, with awareness, to one’s present moment experience.⁴⁹ Mindfulness aims to empower patients to engage in active coping by encouraging them to be aware of the present, where difficult thoughts, feelings, and sensations are acknowledged and accepted without judgement.⁵⁰

Mindfulness based stress reduction (MBSR) may improve pain function in people with chronic pain. MBSR can provide patients with long-lasting skills effective for managing pain.³⁴ Strong evidence shows that MBSR reduces functional disability and improves pain management for a variety of chronic pain conditions including low back pain,⁵¹ fibromyalgia, rheumatoid arthritis, and patients with opioid misuse. The most studied intervention uses an 8-week format of 2-hour/week classes, a 6-hour day in the middle, and daily at-home audio recordings.

The mechanism of action for mindfulness-based strategies is unknown. It seems to be multifactorial, including both physical changes in the stress response system that drive markers of inflammation, as well as psychological mechanisms such as stress resilience and coping.⁵²

Acceptance and commitment therapy (ACT). ACT is a form of CBT. In some cases, trying to control or change pain and thoughts about pain can be counterproductive. ACT is an alternative way to increase acceptance of some of the aspects of chronic pain that may be difficult to alter. Acceptance may free individuals to pursue activities in line with their values.⁵³ The ACT clinical model has six core processes:

1. Acceptance of events and your feelings around them.
2. Perceiving things as they are.
3. Being present and mindful.
4. Observing yourself in context.
5. Identifying personal values.
6. Setting goals based on your values and committing to actions in accordance with those goals.⁵⁴

Various methods of delivering ACT have been shown to be effective in treating chronic pain⁵⁵ either as an individual face-to-face intervention,^56,57 a group-delivered face-to-face intervention,^58–66 via self-help books,^67,68 or through an internet-based delivery.^69–73 ACT based therapy has been shown to decrease pain, improve function, and improve quality of life.

Self-regulatory and psychophysiological approaches. The experience of chronic pain elicits strong physiological reactions that are often accompanied by cognitive thoughts and processes. Several simple techniques harness the connection between the mind and body to improve awareness of and increase control over both psychological and physiological responses to pain.

Techniques include biofeedback, relaxation training, and hypnosis. Biofeedback provides real-time information about physiological processes (eg, heart rate, respiratory rate, muscle tension) with a goal of increasing voluntary control over them. It is often coupled with relaxation training (deep breathing or conscious focusing on relaxation). Biofeedback can decrease the frequency of pain, improve self-management, and decrease use of analgesic medications in both migraine and tension type headaches in adults and adolescents.^74,75 Hypnosis is a state of increased attentional awareness leading to a state of increased relaxation. It has been examined in a variety of pain conditions and found to be effective in decreasing pain most pain conditions, with a reduction in overall pain between 29–45%.^76,77 Effects of specific analgesic hypnotic suggestion were strongest in individuals of high to moderate suggestibility. Most people fall within those two categories, indicating a majority of people would benefit.⁷⁶ A 2020 meta-analysis indicates a possible role for hypnosis in decreasing opioid medication, with hypnosis moderately reducing pain levels coupled with small reductions in opioid dosing.⁷⁸

Integrative Medicine

For interested patients, consider adding historically non-mainstream practices that are evidence-based as part of a multimodal treatment regimen. As evidence emerges regarding the biological role of these treatments, their utility may change.

Integrative medicine is an approach that combines and coordinates conventional medicine with evidence-informed practices that historically are not mainstream. Emerging evidence suggests a role for many less conventional treatments in the management of chronic pain due to their benefits and safety compared to opioid therapy. In addition to previously noted treatments (massage, yoga, tai chi, mindfulness), accumulating evidence supports the use of acupuncture and herbal supplements. More information may be found at the Center for Complementary and Integrative Health at https://nccih.nih.gov/.

Acupuncture. Acupuncture in traditional Chinese medicine uses the insertion of needles into specific areas to manipulate anatomical energetic meridians. The nature of the psychological effect continues to be debated, but efficacy has been established for many chronic pain conditions.⁷⁹ The best evidence exists for osteoarthritis, chronic neck and low back pain, fibromyalgia, and headache. Treatment frequency varies, with the most commonly cited being 1–2 times per week for 4–8 weeks. Some studies show effects lasting 6–12 months.⁸⁰

Herbal supplements. Patients frequently request information about herbal supplements. The evidence for the use of some supplements is growing. Many are safe and may be considered when patients are interested. See Table 6.

Marijuana. Evidence regarding benefits and harms is currently insufficient to recommend using “medical” marijuana for chronic pain. Some data support cannabidiol (CBD) alone as being relatively safe.

With an increasing number of states legalizing marijuana, clinicians and patients are asking about the use of cannabinoids to treat a variety of conditions. The cannabis plant produces many phytocannabinoids, with the highest concentration of these being tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the molecule with psychoactive properties that appears to be responsible for most adverse effects. This remains a challenging and complex area to address. Regulatory and historical factors have resulted in very limited evidence concerning the endocannabinoid system and cannabis pharmacology.

Systematic reviews have found that cannabinoids may be modestly effective for some chronic pain, primarily neuropathic pain, based on limited evidence,^43,44 However, the evidence is largely based on studies of high THC-containing products, which also show high rates of adverse events, such as sedation and psychomotor impairment. In the absence of regulation, the potency and composition of cannabis products are highly variable. Due to these factors, evidence is currently insufficient to recommend using marijuana for relief of chronic pain.

As new evidence begins to emerge regarding the possible role of CBD in analgesia and anti-inflammatory pathways, we may see a role for CBD alone or for products with a high CBD: THC ratio in chronic pain.^81,82 For patients wishing to use CBD alone, some data support CBD as being relatively safe, although there are some potential cytochrome P450 metabolism interactions that should be reviewed. In 2018 the US Drug Enforcement Administration (DEA) reclassified the CBD-based product Epidiolex as Schedule V, which is the least restrictive schedule; however, it is only approved or studied in the setting of two forms of rare seizure disorder. CBD is not recommended for first-line therapy for the treatment of chronic pain. However, patients who have failed other treatments or are opioid dependent may be started on low (5–10 mg twice daily) doses, with slow increases of dose.⁸¹ Of note, these products are not regulated and therefore it is unclear how to determine dose or quality so these products should be considered with caution.

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs (duloxetine, venlafaxine, or milnacipran) can benefit patients with a variety of pain syndromes, including non-specific low back pain, neuropathic pain of various origins, functional abdominal pain, and central pain syndromes such as fibromyalgia. For low back pain, duloxetine at doses up to 120 mg/day reduced both non-specific and neuropathic symptoms. Its mechanism of action seems to be independent of any antidepressant effect. SNRIs are somewhat more effective for functional abdominal pain than tricyclics.⁸⁷ Duloxetine is FDA-approved for diabetic neuropathy and fibromyalgia, though it improves pain scores more than function.

SNRIs are generally well-tolerated, but discontinuing an SNRI requires a gradual tapering down of the dose to avoid withdrawal symptoms, which can occasionally be severe.

Anticonvulsants. Anticonvulsant medications such as gabapentin, pregabalin, and topiramate can be effective for treating neuropathic pain. Dosing can be complex. They have significant adverse effects and are often only modestly effective. Additionally, use topiramate with caution in reproductive-aged women because it increases the risk of cleft lip and cleft palate in newborns.

Pregabalin is approved for the treatment of diabetic neuropathy and fibromyalgia, though it improves pain scores more than function. Gabapentin has only minor benefit in chronic daily headache or migraine. It is not effective in chronic non-specific low back pain.^61,88 Gabapentin and pregabalin are not effective in acute low back pain.

Older anticonvulsants such as carbamazepine and phenytoin have some efficacy for neuropathic pain, but are associated with frequent adverse effects, drug-drug interactions and potentially severe adverse reactions, such as granulocytopenia and hyponatremia.

Pregabalin is a federal Schedule V controlled substance, and gabapentin has been scheduled in many states. Both of these medications produce an increased addiction risk. When combined with opioids, they have been associated with a small increase in death rate. Advise patients treated with gabapentin or pregabalin about increased appetite and the potential for rapid and marked weight gain.

Topiramate at higher doses has been associated with significant speech and cognitive effects

Tricyclic antidepressants (TCAs). TCAs may be potentially useful in a variety of pain syndromes, particularly in neuropathic pain and headaches. They also may benefit comorbid disorders such as insomnia, anxiety, depression, panic disorder, and even smoking cessation efforts. TCAs may have particular use in neuropathic pain, vascular headache prophylaxis, and centralized pain syndromes such as fibromyalgia. Trial data suggest only a modest benefit in functional abdominal pain and less benefit than SNRIs.⁸⁹ In chronic low back pain, low dose TCAs resulted in somewhat less disability at 3 months but had less effect at 6 months.⁹⁰

Doses required for pain treatment are lower than for mood disorders. The lower doses generally avoid problems such as QT prolongation. For patients with sleep initiation problems, taking a TCA at dinnertime rather than bedtime may reduce problems with sleep initiation and with morning fatigue.

When a TCA is used for pain or mood, the time needed for a response can be days to weeks.

TCAs may have adverse effects that can limit their usefulness, such as anticholinergic effects and dysrhythmias. Caution patients about enhanced appetite and the potential for weight gain. Constipation prophylaxis may be needed.

Muscle relaxants. Sedating or non-sedating muscle relaxants are often prescribed for chronic myofascial pain, despite little or no evidence for a long-term benefit.⁸⁸ Cyclobenzaprine, tizanidine, and metaxalone can cause significant sedation, while methocarbamol is less likely to do so. Benzodiazepines pose a significant risk for long-term dependence and misuse, and they substantially increase the danger of overdose when used together with opioids. Baclofen, while somewhat useful for spasticity, has little role as a muscle relaxant, poses a significant risk for dependence, and should generally be avoided.

Topical agents. Topical NSAIDs and anesthetics are occasionally useful in nociceptive or neuropathic pain syndromes. They can be expensive and are often not covered by insurance.

• Topical NSAIDs benefit a minority of osteoarthritis patients. They generally are not useful in other types of pain.^91–93
• Topical lidocaine patches (prescribed or over-the-counter) can be effective. Ointment is less effective and can be messy. Both are expensive and often not covered by insurance. Over the counter 4% lidocaine cream is not expensive, but only marginally effective.
• Capsaicin cream (1%, not 0.25%) can be modestly effective, is available without prescription, but requires care in application to avoid unwanted burning. Compounded capsaicin 8% cream is more effective, but the cost may be prohibitive.
• When other treatments have failed, topical nitroglycerin may have some effect for wound pain, anal fissure pain, vulvodynia, and diabetic neuropathy.
• Compounded topical 5% morphine can provide local wound analgesia and may promote healing. It is only available at compounding pharmacies and can be expensive.

Systemic effects of topical agents are generally minimal. Headache can complicate treatment with nitroglycerin. Avoid nitroglycerin in patients who use phosphodiesterase type 5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil) for erectile dysfunction.

Considerations for Opioid Use

Deciding whether to prescribe opioids is based on an assessment of benefits and harms. While opioids should never be the main treatment for chronic (or acute) pain, in some circumstances, opioids may complement other therapeutic efforts. Important considerations and branching decisions are illustrated in Figure 1 for opioid naïve patients and Figure 2 for patients already on opioids.

Potential Benefit

Assess factors that indicate whether opioids may be beneficial. Based on pain assessment, characterize the patient’s pain based on:

• Time frame: acute, subacute, or chronic.
• Mechanism: nociceptive, neuropathic, central, or a combination of these. Many pain states are the result of a “mixed picture.”
• Pain generators: list each painful area and determine each pain generator.
• Approximate percentage: establish the percentage of pain each pain generator is contributing to the overall clinical status.

A careful history can indicate the types of pain involved and guide treatment plans. For example, if NSAIDs provide significant relief, an inflammatory component to pain is likely. Note whether other modalities and medications have helped or not, and incorporate that information into the treatment plan. Use past experience to guide the decision to start membrane stabilizers (anticonvulsants) and other non-opioid therapies and to determine initial doses. As with all medical decisions, carefully consider risks and benefits.

Short-term opioid therapy may be appropriate for acute pain management to allow for rehabilitation. For chronic pain, opioid therapy is beneficial if it allows a return to function or maintenance of function with minimal adverse effects. If patients are not meeting functional goals during the course of therapy for nonmalignant pain, opioid therapy has failed and should be discontinued.

Potential Risks

Review the patient’s risks and determine if opioid-based therapy is likely to result in harm.

General risks. Potential risks for all patients include:

• Physical adverse effects. Common opioid adverse effects include nausea, constipation, pruritus, respiratory depression, and hot flashes. Chronic opioid use can alter endocrine function and may also lead to dry mouth and subsequent dental caries.
• Cognitive impairment. Patients new to opioids should not drive a vehicle or operate power equipment or heavy machinery until they see how they are impacted by the therapy.
• Social, personal, and family risks. Being an opioid user carries a risk for social stigma. Additional risks are inherent to possessing opioids, including becoming a target for home invasion. Insecure storage may put other family members and pets at risk for opioid poisoning.
• Failing urine drug screening tests. Some jobs require a negative urine drug screen, and employment may not be compatible with opioid therapy. Patient can be harmed financially and professionally if they screen positive for an opioid, even when prescribed and monitored by a clinician.
• Potential for opioid misuse or opioid use disorder.
  • - Patients with depression, anxiety, or a history of substance use disorder are at risk.
  • - Patients with active alcohol use disorder, illicit drug use, or a history of these problems are at risk.

Special populations. Older age, pregnancy, lactation, and chronic illness can impact the safety of opioid medications, so use extra caution with these patient populations. Specific considerations are outlined in Table 8.

Table 8

Special Populations for Whom Opioids Increase Risks. Risks of opioid therapy are higher in these populations. Non-pharmacologic and non-opioid pharmacologic therapies are preferred.

Benzodiazepine and opioids – a safety concern. Generally, do not initiate opioid therapy in patients routinely using benzodiazepine therapy. Both drugs are sedating and suppress breathing. Together they can cause a fatal overdose.

In select cases, co-prescribing may be warranted, such as use of a benzodiazepine for an MRI. In those cases, discuss the risks with the patient. Furthermore, consider the kinetics of each drug relative to the timing of procedures. For example, counsel patients taking hydrocodone daily to skip a dose if they need to take a benzodiazepine for an MRI; benzodiazepines and short-acting opioids should not be taken within two hours of each other. When clinicians inherit patients who are co-prescribed sedatives and opioids, carefully review the relative benefit of each medication and prescribe intranasal naloxone. Consider discontinuing one of the medications.

Marijuana, CBD, and opioids. Discourage concomitant use of THC-containing marijuana products and opioids. The adverse effects of cannabis products may compound similar effects with opioids, leading to safety concerns. Evidence about the combined use of cannabis and opioid prescriptions is limited and inconclusive at present.⁹⁴ If opioids are otherwise indicated, current evidence is insufficient to recommend against prescribing opioids to patients using CBD alone.

Opioid Risk/Benefit Decision

As with all medications, consider the risks and benefits of prescribing an opioid.

Expected functional benefits of opioid use should be clear, with the continuation of opioid therapy dependent on achieving them. While improved sleep and mood are somewhat subjective and should be noted, seek more objective evidence of benefit in order to prescribe and continue opioid therapy. Consider the ability to walk farther, exercise longer, work more, etc. Before initiating opioid therapy, ask patients to identify the functional goals they wish to achieve with opioid therapy, then see if they are meeting these goals at follow up.

Occasionally opioids may have less risk than other pain management medications. Examples include patients vulnerable to gastrointestinal bleeding for whom NSAIDs are contraindicated and patients experiencing cognitive effects from membrane stabilizers.

Drug Selection and Dosing

When the benefits of adding an opioid to other therapy outweigh the risks, select the initial drug and dose based on the:

• Patient:
  • - Opioid naïve or opioid tolerant (ie, has been on ≥ 60 MME/day or 25 mcg/hour transdermal fentanyl for ≥ 7 days)
  • - Patients previously treated with opioids
  • - Special populations affecting dosing
• Drug:
  • - Duration
  • - Potency
  • - Delivery mechanism

All opioids are essentially similar regarding effects and adverse effects. True allergy to any of them is very rare. Morphine and codeine may be slightly less well tolerated, but can be used unless adverse effects become intolerable or a medical contraindication is present.

Opioid naïve patients. In these patients, start with a short-acting opioid at a dose of ≤ 20 MME/day. Over time, the dose may be cautiously titrated. Do not exceed a daily dose of 50 MME.

Opioid tolerant patients. Morphine is the default choice, unless contraindicated. Morphine can be prescribed by all routes, unlike oxycodone. It has a straightforward dose calculation with a predictable analgesic interchange and conversion between parenteral and oral dosing. It is available in long-acting preparations. Cost of all forms of oral morphine is lower, and the long-acting form is covered by all insurances, including Medicaid. The maximum daily dose should not exceed 50 MME. For any doses > 90 MME/day, document the medical justification.

Another option for opioid tolerant patients is buprenorphine, transdermal or buccal. Compared to full agonist therapy, buprenorphine has no ceiling on respiratory depression, generally provides good analgesia, gives consistent serum plasma levels, and does not lead to hyperalgesia or tolerance with the same frequency. Transdermal buprenorphine dosed at 5 mcg/hr (one patch per week) is approximately equal to 20 MME/day. Starting doses of buccal buprenorphine would be 75 mcg once or twice/day. Unfortunately, these options may not be covered by some insurances such as Medicaid.

Transdermal buprenorphine takes approximately 12-24 hours to reach a steady state, during which a short-acting oral opioid may be needed for one-half to a full day, and then should be discontinued. Advise patients to rotate patch locations to avoid skin breakdown. If a rash occurs due to contact with the adhesive, minimize this problem by applying a medium-strength topical steroid such as 0.1% triamcinolone cream to the area 2 hours prior to placement of the patch.

Previous opioids used. If a patient is on multiple opioids, convert to a single opioid when possible. For patients treated with short-acting medications, convert to or add a long-acting medication using the equianalgesic dosing (MME/day) and conversion information in Appendix C. Once the patient is on a long-acting opioid, the short-acting opioid should generally be discontinued.

Dosing for special populations. Older age, pregnancy, lactation, and chronic illness impact the safety of opioid medications, opioid choice, and dosing. Specific considerations are outlined in Table 8.

Naloxone indications. Patients with medical conditions impacting the heart, lungs, or central nervous system are candidates for intranasal naloxone as a rescue strategy. Any patient, regardless of medical comorbidity, who is on > 50 MME/day should also have intranasal naloxone prescribed. Educate family and friends on how and under what circumstances to administer the intranasal naloxone. If a patient is taking benzodiazepines or uses other sedating medications, discuss the risks, prescribe intranasal naloxone, and consider tapering down the opioid dose or converting to an alternative analgesic strategy.

Drug duration and conversion to long-acting preparations. Limit short-acting opioid use over time. If pain persists beyond a few weeks and opioid use is thought to be beneficial, or requiring continuation of greater than 20-30 MME/day, consider converting to a long-acting preparation. Long-acting preparations provide more stable serum levels and slow the development of opioid tolerance. Short-acting opioids used over time result in tolerance more rapidly than long-acting opioids.

Breakthrough Pain. During dose titration, short-acting medication may be provided for breakthrough pain, but should soon be discontinued. In general, when long-acting opioid preparations are prescribed, use of a short-acting opioid should be a few times per month or not at all. Breakthrough dosing should not occur in multiple daily doses. The only exception is during the first few days of titration, when the long-acting medication is being adjusted to a proper steady state dose. This generally takes 3-5 half-lives of the medication.

Frequent initial assessments. Initially see the patient frequently (every 1-4 weeks) to assess their response to the opioid treatment, monitor for adverse effects, assure compliance, and assess for any inappropriate use or behavior. Reminders of the terms of the treatment agreement are useful in this stage.

Reassess the plan in as soon as 2-6 weeks. Keep the dose titration phase relatively short. If after 2-6 weeks, the patient has not achieved satisfactory pain control with a stable dose of medication, refer the patient to a pain management specialist. It is also reasonable to consider discontinuation of opioids at this point, assuming that adequate dosing was given. Opioids do not effectively treat all patients.

Methadone, Buprenorphine, and Fentanyl

These three drugs have special properties and uses deserving special description.

Methadone. Do not use methadone as first-line treatment for chronic pain. Before a clinician prescribes methadone, the clinician should have gained experience monitoring and prescribing it, or should consult a pain specialist.

Special safety hazard and unique advantages. Methadone is unique among opioids, with both increased safety concerns and advantages in long-term therapy. The safe use of methadone requires knowledge of its particular pharmacologic properties. Methadone’s duration of adverse effects far exceeds its analgesic half-life, making it dangerous when combined inappropriately with other controlled substances. Methadone may be useful for patients who require prolonged opioid therapy because it does not tend to require increasingly large doses over time (tolerance). Methadone is also available at relatively low cost.

Many patients are aware that methadone is often associated with opioid addiction therapy. Patients may need additional counseling that methadone is an effective analgesic, not merely a treatment for opioid addiction.

Longer duration affects dose titration. Methadone has a prolonged terminal half-life, so the degree of potential adverse effects can increase over several days after an initial dose or a change of dosage. The duration of methadone analgesia upon initiation may be only 6-8 hours. However, with repeated use, daily to three times daily dosing is effective.

Be cautious when converting from another opioid to methadone (Appendix C).^95,96 As the MME/day rises, the methadone/morphine conversion ratio declines until methadone is approximately twenty times as potent as oral morphine (daily doses of morphine above 500 mg). Refer patients requiring high dose conversions to or from methadone to a specialist in pain management who has experience with methadone dosing.

During the first few days of methadone use, supplemental short-acting opioids may be used to manage inadequate analgesia, then discontinued. Educate the patient about the delayed response of both therapeutic and adverse effects for methadone. For this reason, avoid prescribing benzodiazepines or other sedatives along with methadone. For opioid-naïve patients, initiate methadone at very low doses (< 10 mg/day) divided into twice daily or three times daily dosing. For opioid-tolerant patients, initiate methadone using proper rotation ratios (Appendix C). Starting doses of methadone should not exceed 30 mg/day, even in opioid tolerant patients. Higher dose conversions may be indicated for some patients, but should prompt consultation with a pain management specialist. Regardless of starting dose, titrate (adjust) methadone doses in small increments (max 10-15% of total daily dose) not more often than once every 7 days. Typical methadone dosing for pain is in the range of 5-30 mg/day in divided doses. Higher doses enter the range of opioid addiction treatment.

Effect on QT interval. Methadone can prolong QT interval, especially at higher doses (≥ 100 mg/day) or when used in combination with other medications that prolong QT, including several classes of common antibiotics (eg, macrolides and quinolones). Perform periodic EKG monitoring for patients on higher doses of methadone, and for those being considered for methadone therapy if they are using other QT-prolonging medications (list available at www.qtdrugs.org).

Methadone testing. Methadone, like other opioid analgesics, is associated with a substantial risk for diversion. Mere confirmation of its presence on GC/MS, LC/MS or specific EIA testing (the “opioid” screening test misses methadone) may not be adequate. Prescribers should have a low threshold for periodic testing of serum levels. Specimens should be drawn knowing the variables of patient weight (kg), time since last dose taken (hours), and the total daily methadone dose (mg). Also, be aware of drug interactions that may affect an individual’s methadone clearance. To estimate the expected serum trough level in ng/mL: 263 x total daily dose divided by the patient’s weight. Methadone serum level peaks approximately two hours after dosing and fades over 5-6 hours. A peak level would be approximately double a trough level.

Buprenorphine. Buprenorphine is a partial agonist opioid that is potent and long-acting. Consider prescribing it when a safer, lower adverse effect profile is preferred over full agonist opioids, or for patients who have developed tolerance to other opioids.

Advantages of buprenorphine include its effectiveness, and lack of development of tolerance to it. As a Schedule III drug, it may be written with refills for up to 6 months. Disadvantages include occasional problems with rash from transdermal patch use, and greater expense.

Transdermal buprenorphine (Butrans and generic) is FDA-approved for treating pain. It does not require an XDEA number or training to prescribe. The transdermal form is a good alternative for patients who have developed tolerance to other opioids, had a benefit from opioid treatment but wish to escalate treatment, and are taking ≤ 80 MME/day. Start with a 5 or 10 mcg patch (changed weekly), and discontinue other opioids.

Buccal buprenorphine (Belbuca) is also FDA-approved for pain treatment. It is given twice daily in patients who have previously been treated with opioid up to 160 MME/day. As with transdermal buprenorphine, it is effective, its misuse risk is low and its pharmacokinetics are not complicated. Cost can be a limiting factor.

Sublingual buprenorphine (Suboxone, Subutex and generic) may be prescribed off-label for pain with a regular DEA number. Sublingual buprenorphine has an evolving role, particularly in patients already treated with high dose opioid therapy who continue to complain of uncontrolled pain, and who may or may not have opioid use disorder. It offers a safer, effective option to full agonist opioids, has a lower risk for misuse, produces less opioid tolerance, causes fewer adverse effects, and can enhance mood. Unfortunately, its higher cost and lack of clinician knowledge of its proper use have so far limited its use as a pain treatment.

Initiation of sublingual buprenorphine can provoke acute opioid withdrawal if not done correctly. Therefore, only prescribers trained in its use and in possession of an XDEA number (or working under guidance of such a prescriber) should initiate sublingual buprenorphine/naloxone. Once a patient is on it and stable, primary prescribers may take over chronic management.

Fentanyl. Do not prescribe fentanyl for opioid naïve patients. Only consider prescribing fentanyl in a few unusual situations. Possible examples include: transdermal when gut mu receptors should be avoided; in head and neck cancer when oral intake is challenging; end of life care; intravenous in a patient with intrathecal “pain pump”; buccal and sublingual for episodic and breakthrough end-stage cancer pain.

Transdermal fentanyl (Duragesic and generic) has limited use for treatment of chronic pain. Transdermal fentanyl is a short-acting opioid packaged in a long-acting delivery system, making patients on it especially prone to development of opioid tolerance.

Transdermal fentanyl has a black box warning for opioid naïve patients. It should only be considered, even at low doses, for patients who are tolerant to opioids. Plasma levels of transdermal fentanyl are erratic and are influenced by several factors, including patient temperature, ambient humidity and temperature, skin thickness, presence of adipose tissue, and location of patch. The patch should never be placed on an open wound or mucous membrane. An expired transdermal patch still has a significant amount of fentanyl in it and must be discarded properly.

Dosing of transdermal fentanyl can be complicated; however, a general rule is that the dose of the patch in micrograms x 2 is roughly equivalent to the oral MME/day. For example, a patient on a 50 mcg/hr patch (with a new patch every 3 days) is receiving approximately 100 MME/day (50 x 2 = 100), and a patient on a 100 mcg/hr patch is receiving approximately 200 MME/day, etc. Transdermal fentanyl is commonly available in 12, 25, 50, 75, and 100 mcg/hr patches.

Buccal and lozenge fentanyl. Fentanyl “lollipops” (Actiq) are rapid-acting forms of fentanyl indicated for episodic and breakthrough end-stage cancer pain and generally, should not be prescribed. There is a black box warning on this formulation for using it only in opioid tolerant patients with a cancer-related diagnosis. Unfortunately, it has been used off label with alarming frequency in the last decade.

Fentanyl testing. Fentanyl is a synthetic opioid and its metabolites are often missed in urine drug screens. GC/MS or LCMS are relatively good at detecting it and are reasonable confirmatory tests.

Adverse Effects of Opioid Analgesics

Nearly 80% of patients using opioids experience adverse effects.⁹⁷ The most common adverse effects are sedation, nausea, headache, pruritus, and constipation. Other effects can be confusion, hallucinations, nightmares, urinary retention, dizziness, and headache. Tolerance and regression of most adverse effects often occur quickly. Constipation and urinary retention (smooth muscle inhibitory effects) are more persistent.

The most serious potential adverse effect is respiratory depression accompanied by symptoms of sedation and confusion. It may occur with high dose administration in opioid naïve patients. Opioids, at therapeutic doses, depress respiratory rate and tidal volume. As CO₂ rises, central chemoreceptors cause a compensatory increase in respiratory rate. Patients with impaired ventilatory reserve (COPD, asthma) are at greater risk of clinically significant respiratory depression. Tolerance to respiratory depression develops within just a few days.

In general, all opioids have similar adverse effects, including constipation, nausea, and rash, though constipation may be somewhat worse with oxycodone. For constipation, when initiating opioids, begin constipation prophylaxis using senna or polyethylene glycol 3350. Do not use docusate. During the first few days of treatment, consider antinausea medication. Nausea generally resolves after a few days and may be somewhat more common with codeine. Rash may be more common with morphine.

After an increase in dose, temporary cognitive impairment may occur. Tolerance to adverse cognitive effects usually develops quickly. Cognitive function, including the ability to drive, is preserved when on stable, moderate doses of opioids.

If opioid dosing is > 50 MME/day, prescribe naloxone. Higher opioid dosing increases the potential for overdosing.

With long-term use of opioids, an increased sensitivity to pain (called opioid-induced hyperalgesia) may develop, particularly when doses above those typically prescribed for pain are used. This may be one cause of apparent opioid tolerance, along with true pharmacologic tolerance and disease progression. Fortunately, tolerance to the analgesic effect, when it does occur, develops much more slowly than tolerance to these adverse effects.

Detoxification will likely be required in patients with continued uncontrolled pain on high doses of opioids. Often detoxification can be accomplished by conversion to buprenorphine.

Patient’s Informed Consent and Controlled Substance Agreement

Before starting therapy, establish treatment goals. Focus on small measurable goals that emphasize function. Also discuss the discontinuation plan or “exit strategy” before prescribing. Educate the patient that if the above goals are not being met, then this would be a reason to discontinue opioid based therapy. This discussion is best done during an initial face-to-face visit and can be reiterated on follow up visits.

Prior to prescribing a controlled substance, review the Controlled Substance Agreement (CSA) with the patient. During the review, educate the patient about potential benefits, limitations, and significant risks of the treatment and alternative treatments. Patients must acknowledge that risks exist, that they accept taking those risks, and that they understand what is expected of them if treatment is to be continued. Standards of care for their safety include their submitting urine for toxicology testing and bringing their medication for counting. A CSA does not require a signature. Patients rarely object to a CSA. Any objection is a potential red flag for future problematic behavior. A sample CSA may be found in Appendix B.

In Michigan, laws regarding opioid prescribing require the patient to sign a Start Talking Form, in which they acknowledge in writing that they have been educated about the risks of opioid treatment. This is not the same as informed consent; the Start Talking Form does not meet the legal definition of consent. Instead, it is a document that verifies that education related to the harm of an opioid has been provided to the patient. However, reviewing risks, benefits, and alternatives is a good medical practice.

Advise patients to avoid alcohol while using an opioid. For patients who are pregnant or may become pregnant, discuss the risk of neonatal abstinence syndrome.

Safety Considerations

When to prescribe naloxone for opioid reversal. When opioid therapy is determined to be appropriate, consider prescribing intranasal naloxone as a safety strategy for opioid reversal. Consider naloxone for patients with:

• History of overdose
• History of substance use disorder
• Opioid dose > 50 MME/day
• Comorbidities or factors predisposing to sedation and suppressed breathing (eg, obstructive sleep apnea, significant pulmonary disease, cardiac disease, advanced age)
• Other drugs predisposing to sedation and suppressed breathing (eg, benzodiazepines).

Educate patients, family, and friends. When intranasal naloxone is prescribed, educate the patient and the patient’s family and friends about when and how to use intranasal naloxone and steps after administration. Make sure they all know where naloxone is kept. For very vulnerable patients, consider a medical alert bracelet. Consider advising patients to label for others the location of naloxone in their home, such as a sign on the refrigerator or medicine cabinet.

Storage. Advise patients to store opioid medications in a secure location, preferably locked, that is away from household traffic. Opioids are a common reason for home invasion. Accidental ingestion by children and pets is also a concern.

Advise patients to store naloxone in a location where it can be easily found and accessed by the patient and others in an emergency. Store naloxone in a stable temperature environment in a highly visible and easy to access location. Most preparations of intranasal naloxone have a shelf life of 18 months. Instruct patients and families to check the expiration date frequently.

Disposal. Advise patients how to dispose of unused opioid medications safely and securely. Many options for disposal exist. Having unneeded opioids in the home is a vulnerability for patients and their families. Several disposal locations are available in pharmacies, law enforcement locations, hospital drop boxes, and at community take back events. Local pharmacies may sell over the counter tamper proof drug deactivation bags that can be placed in usual household trash.

Legal Considerations

State and federal laws. Each prescriber must be aware of state and federal laws governing the prescription of opioids and other controlled substances. In Michigan, the law requires several actions by the prescriber when a controlled substance is prescribed.

Occasionally, clinicians may be asked, or are tempted to prescribe opioid analgesics as therapy for opioid use disorder (illicit or prescription). This is illegal. Only prescribers with a XDEA may prescribe buprenorphine for the purpose of treating opioid use disorder. Methadone prescribed for opioid use disorder must be dispensed at a facility licensed by the DEA.

For clinicians interested in obtaining an XDEA number (waiver for buprenorphine prescribing) in the context of treating substance use disorder, contact the Michigan Opioid Collaborative (734-764-0231 or toll free 1-800-525-5188) or consult their website for information on waiver training.

Medicolegal risk. A 2017 review of malpractice claims involving the use of opioids for chronic pain found that a variety of patient and clinician factors contribute to poor outcomes and litigation. Medical comorbidities such as obstructive sleep apnea and cardiopulmonary disease, when combined with a long-acting opioid prescription, was identified as a particularly dangerous combination.⁹⁸ The authors advise that clinicians educate patients about the risks, benefits and alternatives of opioid therapy, perform adherence monitoring, and address aberrant behaviors. Careful documentation and adherence to guidelines are proposed to improve patient safety and minimize legal risk.

Monitoring Visits

An overview of prescribing for patients already taking opioids is presented in Figure 2.

Frequency. After initiating an opioid, see patients within 1-2 weeks, then at least monthly until the patient reaches a stable opioid dose with improvement in pain and function. This allows for close monitoring of opioid adverse effects, adherence and comorbidities.

When the opioid dose is stable with improvement in pain and function, see the patient at regular intervals, but at least every 3 months (CDC guideline).¹¹

Evaluation at each follow up visit. Table 9 provides a checklist of items to accomplish at each visit. Obtain a history and exam to assess the effectiveness of the pain treatment plan as well as the risks and benefits associated with opioid analgesics. Assess pain characteristics, functional status, adverse effects, and adherence to the treatment plan. Review interval diagnostic testing and consults.

Particularly important is information about factors that increase the risk for adverse events or overdose, including decompensation of medical and psychiatric comorbidities, overdose potential, suicidality, as well as active use of other controlled substances, alcohol, marijuana, and illicit drugs.

To facilitate gathering information efficiently, use intake questionnaires or templates within the electronic health record. Consider how to involve clinical team members in the evaluation.

Check the state prescription drug monitoring program report (called MAPS in Michigan) each time a controlled substance is prescribed. Look for multiple prescribers, use of multiple pharmacies, unreported controlled substances, or other red flag behaviors (Table 10).

Urine drug testing. Obtain a urine drug screen (UDS) for all patients on chronic opioid therapy at least once per year, and any time there is a concern for inappropriate use, use of other substances, or diversion.⁹⁹

Urine drug testing is important for verifying the patient is actually using the prescribed medication, and is not selling it or providing it to others (called “diversion”). Urine drug testing also helps with patient safety, by assuring through testing that other sedating substances or medications are not in use. Interpreting test results requires knowledge and care because of the potential for false positive or negative results.¹⁰⁰ When in doubt, consult with your toxicology lab.

Conduct random testing at least yearly and more often if the patient is at additional risk for misuse or diversion for sale. The preferred testing strategy uses a combination of an enzyme linked immunoassay (EIA) for abused illicit substances and gas chromatography/mass spectroscopy (GC/MS) or liquid chromatography/mass spectroscopy (LC/MS). This approach provides the maximum specificity in detecting prescribed or illegally purchased medications that are typically missed by simple screening tests. At Michigan Medicine, order the “controlled medication management panel”.

Three categories of results should raise concern:

• Presence of non-prescribed controlled substances
• Absence of prescribed medications (opioids or other medications)
• Presence of illicit drugs of abuse

Response to these results may include counseling, shortened follow-up intervals and urine testing, pill counts, referral for treatment of substance use disorder, or discontinuation of opioid therapy. See Appendix D for a guide to ordering and interpreting urine drug tests.

Reevaluate the risk/benefit of opioid analgesics. After reviewing the history, exam, and additional data, consider the risks and benefits of continuing opioid therapy. Perform this reevaluation at each visit.

Risk factors may develop during treatment that increase the potential harm of opioid treatment (ie, development of obstructive sleep apnea, new medication interactions, alcohol use, suicidal ideation). Opioids may no longer be resulting in a benefit for pain relief or improvement in functional capacity that warrants the opioid’s risks.

If appropriate, modify opioid dosing. Always use the minimum effective opioid dose, or attempt to taper down the dose. If an increased dose is to be tried, titrate the dose gradually, and do not exceed 50 MME/day unless clear evidence of benefit outweighs the risk. Avoid prescribing more than 90 MME/day (CDC guideline).¹¹ If an increased risk of harm or lack of effectiveness warrants a decrease in opioid dosing, begin a tapering down process. (See section on Discontinuing Opioids below.)

Requests for increases in medication. When patients request increases in opioid medication, perform a full reassessment of any new pain features and changes in psychosocial state. A request for additional opioids could indicate a new or worsened condition, increased tolerance, inappropriate opioid use, diversion, or opioid failure. Check the state prescription drug monitoring program report (called MAPS in Michigan). Perform urine drug testing. Consider doing pill counts. In most cases, avoid escalating opioid dosing for patients who were previously stable on an opioid regimen. A gradual tapering down of the opioid dose or a conversion to buprenorphine may be effective for these patients.

Managing the Prescription of Opioids

Understand regulations for prescribing controlled substances. Know state and federal regulations regarding controlled substance prescriptions. Key features include:

• Schedule II controlled substance prescriptions shall be dated the date written, shall be for up to a one-month supply, cannot be phoned in, cannot have any authorized refills, and are valid for up to 60 days. A clinician may write a prescription dated today, but with instructions that the prescription not be filled for up to 60 days. In general, it is preferable to prescribe up to a 4-week supply (not 30 days), to avoiding marching into weekends. This requires becoming accustomed to writing 28, 56, or 84-count prescriptions.
• Schedule III, IV, and V controlled substance prescriptions may be called in, with up to 6 months of refills.
• All prescriptions shall be created and recorded in the medical record and should be readily retrievable. The information should include date prepared, the desired fill date, dose, quantity, and expected duration of use. E-prescribing is preferred and will soon be a requirement in many states, including Michigan.

Manage prescribing and refills. Establish personal and office policies, roles, and processes that support and facilitate meeting prescribing requirements. An example of policy for controlled substance prescription and refills is presented in Appendix G. The prescriber, patient, clinic staff, and covering prescribers should understand expectations and consequences. There should be no differences from in-person visits managing patients virtually. Video visits are preferred over phone visits and permit pill counts. Covering clinicians should NOT manage controlled substance prescriptions at night or on weekends.

Organize office procedures to meet prescribing requirements. See patients who are on a stable Schedule II-III opioid regimen every 2-3 months. Send in prescriptions to last until the next scheduled appointment or beyond to permit pill counts. For example, on one date, electronically send two 4-week prescriptions and specify a future fill date on one of the prescriptions. For patients taking a Schedule II opioid who are seen every 3 months, utilize clinic personnel to monitor prescription dispensing. Clinic staff can follow a protocol to ensure that the patient is up-to-date with appointments and appropriate monitoring. Staff can prepare a prescription for refill. After the clinician has reviewed appropriate information (including reviewing the state prescription drug monitoring program report), the clinician can electronically sign and send the prepared prescription. In general, best practice is to give refills at face-to-face visits, thereby avoiding excess contacts to the office.

Patients on a stable dose of tramadol (Schedule IV) can be seen every 6 months. Refills for up to 6 months can be authorized on Schedule IV medication prescriptions. To avoid early refills, specify the fill dates for each refill in writing on the prescription.

Assess and Respond to Inappropriate Opioid Use

Assess potential misuse of opioids. Use established criteria to evaluate misuse of opioids by chronic pain patients receiving long-term opioid therapy.¹⁰¹ Meeting 3 or more of the following criteria is defined as misuse.

1. Focus on opioids. The patient displays an overwhelming focus on opioids during visits. This focus occupies a significant proportion of the clinic visit time and impedes progress on other issues regarding the patient’s pain. This behavior must persist beyond the third clinic treatment session.
2. Early refills. The patient demonstrates a pattern of requesting early refills (3 or more) or escalating drug use in the absence of an acute change in his or her medical condition.
3. Multiple contacts about opioids. The patient generates multiple telephone calls, visits, or other contacts to the administrative office requesting more opioids or early refills, or for problems associated with the opioid prescription.
4. Prescription problems. There is a pattern of prescription problems for a variety of reasons that may include lost, spilled, or stolen medications.
5. Multiple sources of opioids. The patient has supplemental sources of opioids obtained from multiple clinicians, emergency rooms, or illegal sources.
6. Other substance misuse. Concurrent illicit substance use or alcohol use disorder.

The authors of these criteria reported that 34% of chronic pain patients on opioids met at least one criterion, and 27% met 3 or more. These and other red flag behaviors are listed in Table 10.

Evaluating inappropriate opioid use. Respond to aberrant behaviors by collecting more information and discussing with the patient. Tools such as the drug abuse screening test (DAST-10) or Michigan opioid risk assessment (MORA) can be helpful in this effort. Check the state prescription drug monitoring program report. Perform a urine comprehensive drug screen to check for both the presence of non-prescribed medications or illicit substances and for the presence or absence of prescribed controlled substance medications. If opioid diversion is confirmed, discontinue the opioid prescription immediately. In most cases of opioid misuse, discontinuing opioid prescribing is indicated, using either a rapid or slow taper (see Discontinuing Opioids). Evaluate those patients who misuse opioid prescriptions for the presence of complex persistent dependence or opioid use disorder, and offer treatment.

Complex Persistent Dependence

The gray area between dependence and addiction can be challenging for clinicians and patients. A 2012 article by Ballantyne, et.al. proposed a classification of complex persistent dependence that explains the pathophysiology accounting for worsening functional status and pain in patients on long-term opioid therapy.¹⁰²

When attempting to taper down opioid dosing for a patient with complex persistent dependence, aberrant behaviors and fluctuation in opioid use can occur. The development of protracted abstinence syndrome may lead to worsening pain, declining function, and worsening psychiatric symptoms. Paradoxically, the same symptoms may occur with maintenance of long-term high dose opioid therapy. Pain relief is more complex than analgesia measured by pain scales. Pain relief involves relief in the affective component of the pain experience, as mediated through mesolimbic reward and learning pathways involving the endogenous opioid system. This system is distinct from the pathways involved in nociceptive input. The same endogenous opioid pathways involved in reward are also involved in relief from other experiences including frustration, anger, anxiety, and despair. While analgesics like acetaminophen are thought to have effects on the analgesic pathways involved in nociception, opioids have additional effects on pathways that mediate relief. Opioids have a dual role in mediating direct relief on both analgesic pathways and reward pathways.

Some evidence shows that patients with complex persistent dependence may tolerate transition to buprenorphine better than a tapering down of the opioid dose. When complex persistent dependence is suspected, a more clinically useful approach may be to transition to buprenorphine and then taper down the dose. Start with careful communication with the patient about this strategy, including reassurances that the patient is not being treated “like an addict,” and then refer to a buprenorphine waivered prescriber.

Some evidence exists for methadone use in this population as well. However, it is less promising than buprenorphine.

Opioid Use Disorder in Pain Patients

Substance use disorder complicating the treatment of chronic pain. The prevalence of substance use disorder among patients with chronic pain is significant. Studies have repeatedly demonstrated that at least 20% of opioid-treated patients misuse or divert their medication. In one survey 70% of patients reported not taking their opioids as prescribed, often using them up quickly, then going without or obtaining opioids in illicit ways until due for their next refill.^103,104

Use drug misuse risk screening tools (such as the DAST-10) to help identify patients for whom risk might be managed by more frequent follow-up visits, checks of the state prescription drug monitoring program report, urine drug testing, or pill counts. However, these measures are imperfect. Risk screening tools can also aid in the decision that opioid risk exceeds the limited benefit for improving a patient’s functional state.

A full discussion of the diagnosis and management of opioid use disorder is beyond the scope of this guideline. However, monitor patients for signs and symptoms of this disorder. Watch for red flag behaviors that may indicate addiction or diversion. Apply the DSM-5 diagnostic criteria to diagnose opioid use disorder, as listed below. (Mild opioid use disorder: 2-3 symptoms; moderate: 4-5 symptoms; severe: 6 or more symptoms):

• Opioids are often taken in larger amounts or over a longer period than intended.
• There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
• A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.
• Craving, or a strong desire to use opioids.
• Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home.
• Continued opioid use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
• Important social, occupational, or recreational activities are given up or reduced because of opioid use.
• Recurrent opioid use in situations in which it is physically hazardous.
• Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by opioids.
• Tolerance, as defined by either of the following: (a) a need for markedly increased amounts of opioids to achieve intoxication or desired effect, or (b) markedly diminished effect with continued use of the same amount of an opioid.

Principles for managing opioid use disorder in pain patients. The treatment of pain patients who exhibit evidence of opioid use disorder requires heightened monitoring, or discontinuation of opioid therapy and initiation of addiction treatment. Successful treatment depends on the clinician understanding that opioids provide more than analgesia, and that loss of control is not a moral failure by the patient, but a known complication of a reinforcing medication.

• Have a frank but supportive discussion with the patient about the fears of a worse lifestyle and risk for overdose. Offer support and addiction treatment.
• Provide support. A patient should not be made to feel judged, scorned, or abandoned by a clinician just because a diagnosis of opioid use disorder is made.
• Consider buprenorphine. For patients with opioid use disorder, conversion from other opioids to buprenorphine can provide a safer alternative while still providing the benefits, if any, of opioid analgesia. This can be done by a prescriber with a XDEA, with input from other specialists as needed.
• Refer when needed. If the complexity of a patient’s management exceeds the capability of the prescriber, refer for formal addiction treatment.
• Do not continue to prescribe full agonist opioids for patients who exhibit loss of control over proper medication use or who use illicit substances. The risks for overdose or diversion outweigh any benefit.
• Prescribe naloxone and instruct the patient, family, and friends on its proper use.

When to Refer to a Pain or Addiction Specialist

When the management of patients with chronic pain involves difficult clinical or behavioral problems, refer the patient to an appropriate specialist or to multidisciplinary management.

Clinical problems for referral include:

• Outcome failure. Failure to attain adequate pain relief to achieve functional improvement goals after 6 weeks of opioid analgesic dose titration.
• Adverse events. Ongoing adverse effects of opioid therapy.
• Unexpectedly large doses of opioids required.
  • - Doses beyond what the primary care clinician is comfortable prescribing or beyond what are considered typically adequate for most pain management.
  • - Upper limits typically prompting referral are opioids in combination that exceed a total daily dose > 90 MME/day. (See Appendix C.) Also refer for individual medication doses greater than morphine 90 mg/day, hydrocodone 90 mg/day, oxycodone 60 mg/day, fentanyl 50 mcg/hr, hydromorphone 16 mg/day, methadone 30 mg/day.
• Breakthrough dosing. The patient requires additional dosing for breakthrough pain more than a few times per month.
• Opioid-induced hyperalgesia.
• Opioid overdose
• Need for conversion to sublingual buprenorphine if high opioid doses or insurance do not permit use of transdermal or buccal buprenorphine.

Behavioral problems for referral include:

• Persistent behavior suspicious for addiction or diversion.
• Non-adherence with the Controlled Substance Agreement.

Reasons for Discontinuing Opioids

Opioids may be discontinued for a variety of reasons, including diversion, prescription forgery or fraud, non-adherence to the treatment plan, lack of benefit, excessive dosing, a need to convert multiple opioids to a single opioid, or hospitalization. Opioid tapering and discontinuation can be challenging. Carefully consider each patient’s medical, psychological, financial, and intellectual factors.

Speed of Discontinuation

The speed with which opioids are stopped depends on the situation. Options include immediate discontinuation, rapid taper, slow taper, buprenorphine conversion, and referral to an addiction specialist. See Appendix F for more information about these actions, along with associated reasons and recommended processes.

Immediate discontinuation. If controlled substance diversion, prescription forgery or fraud is discovered, immediately discontinue opioid prescribing. DEA regulations require that diversion for sale or prescription fraud be reported, so when these illegal activities are suspected, notify local law enforcement. Immediate discontinuation of opioids is also appropriate if there are dangerous behaviors with potential for immediate harm. Example situations include motor vehicle accident or arrest due to opioid or illicit drug or alcohol intoxication, intentional overdose, or suicide attempt. Aggressive or threatening behavior in the clinic can also be grounds for immediate discontinuation of opioids. When immediate discontinuation of opioid therapy is necessary, inpatient detoxification can be offered to help treat withdrawal.

Rapid taper. If a patient is not following appropriate use instructions, using a rapid taper to discontinue will prevent opioid withdrawal. The amount of opioid necessary to prevent withdrawal is only 20% of the previous day’s dose (based on rapid detoxification studies). However, a rapid taper that reduces the dose by 25-50% per week over 2-4 weeks is commonly practiced.

Slow taper. If opioid treatment provides no benefit or produces clinical harm, discontinue with a slow taper to avoid withdrawal symptoms. The general rule for a slow taper is similar to initiation of therapy: use adjunct medications and non-pharmacological options (distraction, acupuncture, procedures, etc.) to help facilitate the tapering down process. Tapering down can be challenging, and patients may require frequent visits for reassurance or adjustments. Moreover, some opioid medications only are available in larger doses. Later in the tapering down process, converting to short-acting medications may be desirable to allow smaller dose changes over time. Generally, a slow taper that reduces the dose by 10% per week will prevent withdrawal, but it is important to know that the approach to tapering down must be individualized.

Explain Discontinuation

Prior to discontinuing an opioid, explain the tapering down process and the reasons for discontinuation. Some evidence shows that patients prefer to get this information from their primary care clinician or a clinician with whom they have a close relationship. Often, a patient’s need for an intranasal naloxone rescue strategy can be used to initiate and inform the conversation about why that patient may need to taper down the opioid dose. Providing a written taper schedule may be helpful. Scheduling regular check-in phone calls or telehealth visits can facilitate ongoing communication and increase adherence to a tapering down plan.

Complex Discontinuation

When a simple tapering down of the opioid dose is not feasible, consider referral to a specialist in addiction medicine. It is important to discuss the reason for this with the patient, addressing the social stigma of addiction and the rationale for referral.

National Guidelines

This guideline is generally consistent with the:

Institute for Clinical Systems Improvement (ISCI) guideline on Pain: Assessment, Non-Opioid Treatment approaches and Opioid Management. Best evidence for topics: recommendations and key references, pages 9 – 16.

Performance Measures

National and regional programs that have a clinical performance measure for care for the management of pain include the following.

• Centers for Medicare & Medicaid Services:
• Blue Cross Blue Shield of Michigan (BCBSM)
• Blue Care Network [HMO]: clinical performance measures (BCN)

While specific measurement details vary (eg, method of data collection, population inclusions and exclusions), the general measure is:

Documentation of Signed Opioid Treatment Agreement: All patients 18 and older prescribed opiates for longer duration than 6 weeks who signed an opioid treatment agreement at least once during Opioid Therapy documented in the medical record (CMS).

Funding

The development of this guideline was funded by UMHS.

Guideline Development Team and Disclosures

The multidisciplinary guideline development team consisted of:

• Primary care clinicians: Daniel W. Berland, MD, General Internal Medicine/Addiction Medicine; Jill N. Fenske, MD, Family Medicine.
• Specialists in pain management care: SriKrishna Chandran, MD, Physical Medicine & Rehabilitation, Pain Medicine; Paul E. Hilliard, MD, Pain Medicine, Anesthesiology.
• Consultant specialists: Kimberly C. Bialik, PhD, Psychological Aspects of Pain Management; Daniel J. Clauw, MD, Anesthesiology, Internal Medicine-Rheumatology; Eve D. Losman, MD, Emergency Medicine; Kathleen S. Mehari, MD, Obstetrics & Gynecology; Michael A. Smith, PharmD, College of Pharmacy; and Susan Urba, MD, Hematology/Oncology.
• Guideline development methodologist: R. Van Harrison, PhD, Learning Health Sciences.
• Literature search services were provided by informationists at the Taubman Health Sciences Library, University of Michigan Medical School.

UMHS endorses the Standards of the Accreditation Council for Continuing Medical Education that the individuals who present educational activities disclose significant relationships with commercial companies whose products or services are discussed. Contributions of team members with relevant financial relationships are reviewed by team members without relevant financial relationships to assure the information is presented without bias.

None of the team members or consultants have relevant personal financial relationships.

Systematic Review of Literature

A detailed description of the systematic search and review of literature upon which this guideline is based is presented in the associated UMHS document “Ambulatory Pain Management, 2019: Literature Review Methods and Results.” The following section highlights major aspects of the literature search and review process.

Literature search. The team began the search of literature by accepting the results of a systematic literature review performed in 2016:

Institute for Clinical Systems Improvement (ISCI) guideline on Pain: Assessment, Non-Opioid Treatment approaches and Opioid Management. Best evidence for topics: recommendations and key references, pages 9 – 16.

To update those results, we performed a systematic search of literature on Medline and in the Cochrane Database of Systematic Reviews for the time period 1/1/16—10/2/18.

The major search terms were acute and subacute pain, and chronic pain (non-terminal). The searches were for guidelines, controlled trials (including meta-analyses), and cohort studies, for literature on humans in the English language. Within these parameters individual searches were performed for the following topics:

Major Topic: Acute and Subacute Pain

• A. Acute and Subacute Pain: Etiologies of acute/subacute pain, Non-opioid therapies for acute/subacute pain, Use of opioids for acute/subacute pain, Universal precautions for opioid therapy, Acute and subacute pain, not included in A.

Major Topic: Chronic Pain (non-terminal)

• B. Chronic Pain Assessment: Pain characteristics (location, quality, intensity, time course), Pain treatment history, Determination of pain generator (focal pain generator, neuropathic pain, centralized pain syndrome), Quality of life and functional impact, Comorbidities (medical, psychiatric, substance use disorders), Pain beliefs and response to pain, Social determinants (adverse childhood experiences, psychosocial stressors), Chronic pain assessment, not included in B.
• C. Designing an Individualized Pain Treatment Plan: Multimodal interventions, Clinician-patient communication (shared decision-making, team approach), Individualized plan, not included in C.
• D. Non-Pharmacologic Treatments/evidence: Lifestyle management (exercise, sleep hygiene), Physical therapy, Other physical modalities (TENS, massage), Complementary and alternative therapies, Psychological interventions (mindfulness, CBT, etc.), Non-pharmacologic treatment, not included in D.
• E. Non-Opioid Pharmacologic Treatment: Acetaminophen, NSAIDs, Tricyclic, SNRI, Anticonvulsants, Muscle relaxants, Topicals not included in E, Non-opioid pharmacologic treatment, not included in E.
• F. Rational Use of Opioids in Chronic Pain; Decision Phase: Risk-benefit analysis (patient selection, risk analysis, informed consent), Assuming care for patients already on opioids, Special populations (pregnancy/lactation, geriatrics, renal disease, liver disease, pediatrics). (No search for “other”)
• G. Rational Use of Opioids in Chronic Pain: Initiation and Treatment Phase: Drug selection and dosing (general guidance, CDC guidelines [most important example of general guidance]), Methadone, Fentanyl, Buprenorphine, Adverse effects, Controlled substance agreement, Safety considerations (avoid co-prescription with benzodiazepine, naloxone, storage, disposal), State of Michigan controlled substance legislation (no search), Opioids initiation/treatment, not included in G.
• H. Rational Use of Opioids in Chronic Pain: Maintenance Phase: Monitoring (frequency of visits, prescription drug monitoring programs, urine drug screening), Opioid refill management (office procedures), Assessing potential problems with opioid therapy, Response to suspicion for opioid misuse or diversion, Indications for referral to pain/addiction specialist, Legal issues, Medical marijuana, Opioid maintenance, not included in H.
• I. Tapering/Discontinuation of Opioids: Best practice for communication with patients about tapering, General tapering guidelines, Complex persistent dependence, Persistent abstinence syndrome, Opioid tapering/discontinuation, not included in I.
• J. Opioid Use Disorder: Detection, diagnosis, treatment (medication-assisted therapy), referral options, Chronic pain and opioids, not in J, Chronic pain, not included in J.

A more formal presentation of the inclusion and exclusion criteria is in Section II of the accompanying Literature Review Methods and Results.

The detailed search strategies are presented in Section III of the accompanying Literature Review Methods and Results.

The search was conducted in components of a formal problem structure (outlined above). The search was supplemented with very recent clinical trials known to expert members of the panel. The search was a single cycle. The number of publications identified is presented in Section IV of the accompanying Literature Review Methods and Results.

Literature review and assessment. Members of the guideline team reviewed the publications identified to be relevant to specific topics in order to select those with best evidence. Criteria to identify overall best evidence included relevance of the study setting and population, study design, sample size, measurement methods (variables, measures, data collection), intervention methods (appropriateness, execution), appropriateness of analyses, and clarity of description.

In considering level of evidence based on study design, the classification was:

• A = systematic reviews of randomized controlled trials with or without meta-analysis
• B = randomized controlled trials
• C = systematic reviews of non-randomized controlled trials or observational studies, non-randomized controlled trials, group observation studies (cohort, cross-sectional, case-control)
• D = individual observation studies (case study or case series)
• E = expert opinion regarding benefits and harm.

Beginning with best evidence identified by the ISCI systematic literature review, team members checked publications identified in the more recent search (1/1/16—10/2/18) to determine whether better evidence was available. Team members also had the option of considering very recent literature (published since 10/2/18) in determining whether even better evidence was available.

The process of review and assessment is described in more detail in Section V of the accompanying Literature Review Methods and Results.

Best evidence and recommendations. Team members identified articles or other publications with best evidence regarding specific topics.

The guideline team reviewed the evidence and determined the importance of performing or not performing key aspects of care (listed on the first page of this guideline). In the absence of empirical evidence, the guideline team based recommendations on their expert opinion.

The strength of recommendations regarding care were categorized as:

• I = Generally should be performed
• II = May be reasonable to perform
• III = Generally should not be performed.

Section VI of the accompanying Literature Review Methods and Results presents a table of each recommendation and the source of best evidence on which the recommendation is based.

Review and Endorsement

A draft of this guideline was reviewed by units within UMHS to which the content is most relevant. Pharmacy Services performed the initial review. Then reviews occurred in clinical conferences or by distribution for comment within the following clinical departments and divisions: General Internal Medicine, Family Medicine, Physical Medicine & Rehabilitation, Pain Medicine, Anesthesiology, Clinical Psychology, Emergency Medicine, Obstetrics & Gynecology, Hematology/Oncology, and the Controlled Substances Quality Improvement Committee. The draft was revised based on comments from these groups.

The final version of this guideline was endorsed by the Clinical Practice Committee of the University of Michigan Medical Group and by the Executive Committee for Clinical Affairs of the University of Michigan Hospitals and Health Centers.

Appendix A1. Body Map

Appendix A2. PEG Scale Assessing Pain Intensity and Interference (Pain, Enjoyment, General Activity)

Appendix A3. Chronic Pain Assessment Questionnaire

Appendix A4. Outline for Follow-up Visits for Patients with Chronic Pain

Appendix A5. DAST-10

Appendix A6. MORA

Appendix B. Patient-Clinician Agreement

Appendix C. Oral Opioid Dose Equivalents and Conversions

Typical oral (every 4 hours) doses of short-acting opioids shown as equivalents to morphine:

Appendix D. Ordering and Interpreting Urine Drug Tests

When initiating or monitoring opioid therapy, two tests are often required. The two complimentary tests are the enzyme linked immunoassay (EIA) kit and gas or liquid chromatography/mass spectrometry (GC/MS or LC/MS). They provide different information.

• Illicit drugs: EIA
• Confirm taking prescribed meds (specify meds when order test): GC/MS or LC/MS. (EIA will provide this information if your laboratory runs the test for each med. However, laboratories usually do not. Ask!)
• Use of non-prescribed medication: GC/MS or LC/MS
• Testing for heroin: GC/MS. Check for one of its specific metabolites, eg, 6 monoacetyl morphine (6-AM) duration 2-4 hours only is positive as morphine in 2-3 days

Appendix E. Summary of Michigan Legislation Related to Controlled Substance Prescribing

Appendix F. Discontinuing Opioids

Appendix G. Example Clinical Policy

Appendix H. Resources and Websites

Information About Chronic Pain

Managing Your Child’s Chronic Pain, by Tonya Palermo is a good example of a book that provides sound scientific knowledge and practical advice for parenting youth who have ongoing pain.

When Your Child Hurts, by Rachel Coakley provides families with basic information about what chronic pain is and how to deal with issues like, “How much do I push my child?”, “Do I still make them go to school?” And other common issues faced by parents.

These books are not designed to replace good cognitive behavioral and family therapy, but can be good additions to the work done in therapy.

The Chronic Pain and Illness Workbook for Teens, by Rachel Zoffness is designed specifically for teens who deal with chronic pain and fatiguing conditions. It takes the best of what we know about CBT and helps the teen apply it to their lives

Several websites designed to provide basic information about chronic pain and its treatment are listed below:

This online program is Cognitive Behavioral Therapy (CBT) based and can be done with or without a pain-trained therapist.

PainBytes

http://www.aci.health.nsw.gov.au/chronic-pain/painbytes

A great option for treatment of Chronic Pain among adolescents is the WebMAP Mobile App. CBT and use of the techniques in the app have been shown to decrease pain, increase functioning and improve quality of life. Get it now in the App Store.

A good general website with resources for helping families cope with chronic pain is the www.MegFoundationforPain.org

A good general explanation of chronic pain: https://www.youtube.com/watch?v=C_3phB93rvI

A good resource for teachers is http://teachpain.wordpress.com/pain-101/

Finding a Local Counselor

https://umcpd.umich.edu/

ADAA - https://members.adaa.org/page/FATMain

CHRONIC PAIN COPING RESOURCES

Books: Pain is really strange by Stephen Haines

Websites:

Neuroplasticity Transformation: Dr. Moskowitz and Dr. Golden

Curable App

American Chronic Pain Association

U of M Fibro Guide

Palouse Mindfulness

https://mobile.va.gov/appstore/mental-health for various apps

The VA has a page specific to chronic pain https://www.va.gov/PAINMANAGEMENT/Veteran_Public/CHRONIC_PAIN_101.asp

Data Availability

These links to Internal UMHS Guidelines contain proprietary information so are only accessible to appropriate Michigan Medicine staff. For more information, contact the authors or publisher.

Supplementary material can be found at http://www.uofmhealth.org/provider/clinical-care-guidelines