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National Clinical Guideline Centre (UK). Spinal Injury: Assessment and Initial Management. London: National Institute for Health and Care Excellence (NICE); 2016 Feb. (NICE Guideline, No. 41.)
17.1. Introduction
Spinal cord injury (SCI) has a number of devastating and disabling consequences, with up to 40% of patients developing a chronic neuropathic pain (NP). Most cases of NP begin during the acute rehabilitation stage and can cause further detrimental effects to the patient’s quality of life. Pharmaceutical management strategies of NP after symptom onset have had limited success, commonly resulting in a pain reduction of only 20–30%.
Pre-emptive analgesia of the nervous system, in the acute stages of SCI, may provide a greater clinical efficacy as the mechanism driving pain tends to be refractory and its treatment suboptimal following onset. A number of animal studies have demonstrated a reduction in chronic pain with early intervention prior to symptom onset but it is unclear if these findings have translated into humans.
17.2. Review question: What are the optimum strategies given in the acute management stage to prevent later neuropathic pain in people with traumatic spinal cord injury?
For full details see review protocol in Appendix C.
Table 74PICO characteristics of review question
| Population | Children, young people and adults with traumatic SCI |
|---|---|
| Intervention/s |
|
| Comparison/s |
|
| Outcomes | Critical:
|
| Study design | RCTs or systematic reviews of RCTs |
17.3. Clinical evidence
One study was included in the review101. Evidence from this study is summarised in the clinical evidence summary below (Table 76). See also the study selection flow chart in Appendix D, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in Appendix J.
Table 75
Summary of studies included in the review.
Table 76
Clinical evidence summary for carbamazepine versus placebo.
The single study identified compared carbamazepine with placebo in patients with acute SCI. The intervention was administered within 2 weeks of the injury in patients who had not yet developed NP symptoms. The intervention was continued for 1 month only, and patients followed until 6 months post injury.
No relevant clinical studies comparing amitriptyline, trazodone, duloxetine, venlafaxine, lamotrigine, mexiletine, gabapentin, pregabalin, topiramate, sodium valproate, clonidine, levetiracetam, ketamine, alfentanil or lidocaine with placebo or no treatment were identified.
17.4. Economic evidence
Published literature
No relevant economic evaluations were identified.
See also the economic article selection flow diagram in Appendix E.
Unit costs
For the majority of drugs listed in the protocol, the dose is unknown, either because clinical evidence was not identified to be able to identify the dose, or because the drugs are used for other reasons primarily and thus, the dose for NP may not be the same as for then other uses of the drug.
Prices vary but are generally quite low, the highest priced drug being pregabalin costing £96.60 for 84×50 mg tablets{NHS Business Services Authority, 2014 NHSEDT/id}.
17.5. Evidence statements
Clinical
Moderate quality evidence suggested a clinical benefit for carbamazepine when compared with placebo in improving the rate of absence of NP or presence of mild NP at 1 month but no clinical difference at 6 months (1 study, n=44).
Moderate and Low quality evidence suggested a clinical benefit for carbamazepine when compared with placebo in improving the rate of moderate to severe NP at 1 month and 6 months, respectively (1 study, n=44).
Moderate and Low quality evidence suggested no clinical benefit in carbamazepine when compared with placebo for improving the SF-36 quality of life scores (bodily pain, physical function, social function, vitality, emotional performance, physical performance, general health state and mental health) (1 study, n=44).
Low quality evidence suggested no clinical difference between carbamazepine and placebo in rates of the adverse events nausea, vomiting and visual disturbance (1 study, n=44).
Moderate and Low quality evidence suggested a clinical benefit of carbamazepine when compared with placebo for improving the rate of people free from depression and mild depression (1 study, n=44). Low quality evidence suggested no clinical difference between carbamazepine and placebo in improving rates of moderate or severe depression (1 study, n=44).
Economic
No relevant economic evaluations were identified.
17.6. Recommendations and link to evidence
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered mortality, pain, quality of life and the adverse events, dizziness and visual disturbance, nausea and vomiting, and lethargy, to be the most important outcomes to inform decision making for this review. These specific adverse events were chosen as the most common and potentially harmful effects of the pharmacological agents investigated. Of these critical outcomes, the GDG agreed that a reduction in mortality rates would be unlikely with these therapies. The purpose of these pharmacological agents is to relieve pain and this mechanism would have no effects on improving survival, neither is mortality a common associated effect of these agents. Although patient-reported outcomes, such as psychological wellbeing, including depression and anxiety were felt to be important, they were not critical to the decision making. The GDG felt, in the context of NP in spinal injuries, that psychological wellbeing as an individual outcome and not as part of a quality of life measure would not adequately reflect the effects of prevention of NP. |
| Trade-off between clinical benefits and harms | The GDG felt that the benefits of reduced rates of moderate and severe NP and mild depression could outweigh the low rates of relatively minor (nausea, vomiting and visual disturbance) adverse events reported for carbamazepine. However, the GDG expressed surprise that the only evidence was for carbamazepine, as gabapentin or pregabalin is more commonly the potential treatment choice. The GDG concluded that the limited evidence made it difficult to make a judgement on the relative benefits or harms of the different medications. |
| Economic considerations | No economic evidence was identified for this question. There is likely to be a difference in resource use in terms of the cost of the medication for prevention of neuropathic pain. The presence of NP will have an impact on the patient’s quality of life downstream and potentially affect the capacity for them to undertake their normal activities pain free. Carbamazepine has some benefit in helping with depression, this could contribute to the overall improvement in quality of life as anxiety or depression/mental health are generally captured on health-related quality of life measures. On the other hand, it is also important to consider adverse events from the medications. Although the adverse events were relatively minor and would not have a big impact on resources (for example, vomiting, nausea), these will impact on a patient’s quality of life and there may be a point at which a patient feels the risks are outweighing the benefits of taking the intervention. The clinical study identified also reported quality of life data using the SF-36. It was discussed with the GDG whether it would be useful to estimate the cost effectiveness of carbamazepine versus placebo using this data. However the GDG were not very confident about the paper and it was decided that estimating the cost effectiveness using this paper would not add value or help them in making their recommendation. Overall, the GDG agreed that there was positive evidence for carbamazepine, with the benefit likely to outweigh the risks. As the intervention is relatively low cost, it is therefore potentially cost effective compared with not taking it. However, as clinical benefit was ascertained using an isolated study, the GDG felt the uncertainty was too great to make a positive recommendation. |
| Quality of evidence | Only one study investigating the prevention of NP in patients with acute SCI was identified. The comparison was between carbamazepine and placebo; no other studies comparing other preparations were identified. The quality of evidence for outcomes reported in this review ranged from Moderate to Low. Quality was not downgraded due to risk of bias. Having adequate allocation concealment, blinding, low attrition and use of validated outcome measures the risk of bias in the included study was low. Quality was, however, downgraded due to imprecision of the effect estimates. The width of the confidence intervals and thus the uncertainty of the estimate reflects the relatively small number of participants in the study. It was noted by the GDG that the data were from one single study, and that the sample size was so small. The imprecision of the effect estimates was also a significant weakness considered in the discussion. The GDG also discussed concerns that the control group rate of NP, in their experience, was not representative of background rate of NP in SCI patients, suggesting that this may be a specific, narrower population than suggested. The GDG reflected that, should this be the case, the number needed to treat would rise and therefore the balance of harms and benefits may be reversed. Regarding the study design, the GDG felt that in not measuring the initial burden of somatic pain in each group, there may have been hidden significant baseline differences as a source of bias. The GDG were also concerned that the treatment was only continued for 1 month and, while apparent benefits of the treatment were greatest at the 1 month follow-up, this benefit was not maintained at the 6 month follow-up. |
| Other considerations | These medications have been used for the treatment of NP for some time (see NICE Clinical Guideline 173 Neuropathic pain – pharmacological management: The pharmacological management of neuropathic pain in adults in non-specialist settings). However, their use to prevent NP before it has occurred is an emerging area and there is limited evidence to support a positive recommendation. Given the limitations of the evidence, the GDG were unable to recommend carbamazepine as a preventative treatment and proposed a research recommendation. The GDG emphasised the importance of providing adequate pain relief in the acute stage of injury. See major trauma guideline chapter 14. |
- Neuropathic pain - Spinal Injury: Assessment and Initial ManagementNeuropathic pain - Spinal Injury: Assessment and Initial Management
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