Herbal medicinal products or preparations for neuropathic pain Edited (no change to conclusions)
Neuropathic pain is a consequence of damage to the central nervous system (CNS), for example, cerebrovascular accident, multiple sclerosis or spinal cord injury, or peripheral nervous system (PNS), for example, painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), or surgery. Evidence suggests that people suffering from neuropathic pain are likely to seek alternative modes of pain relief such as herbal medicinal products due to adverse events brought about by current pharmacological agents used to treat neuropathic pain. This review includes studies in which participants were treated with herbal medicinal products (topically or ingested) who had experienced neuropathic pain for at least three months.Objectives
To assess the analgesic efficacy and effectiveness of herbal medicinal products or preparations for neuropathic pain, and the adverse events associated with their use.Search methods
We searched CENTRAL and the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL and AMED to March 2018. We identified additional studies from the reference lists of the retrieved papers. We also searched trials registries for ongoing trials and we contacted experts in the field for relevant data in terms of published, unpublished or ongoing studies.Selection criteria
We included randomised controlled trials (including cross‐over designs) of double‐blind design, assessing efficacy of herbal treatments for neuropathic pain compared to placebo, no intervention or any other active comparator. Participants were 18 years and above and had been suffering from one or more neuropathic pain conditions, for three months or more.
We applied no restrictions to language or gender. We excluded studies monitoring effects of isolated, single chemicals derived from the plant or synthetic chemicals based on constituents of the plant, if they were not administered at a concentration naturally present within the plant.
We excluded studies monitoring the effects of traditional Asian medicine and Cannabinoids as well as studies looking at headache or migraine as these treatments and conditions are addressed in distinct reviews.Data collection and analysis
We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion, assessed risk of bias, and extracted data. We calculated the risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNTB). The primary outcomes were participant‐reported pain relief of 30%, or 50%, or greater, and participant‐reported global impression of clinical change (PGIC). We also collected information on adverse events. We assessed evidence using GRADE and created a 'Summary of findings' table.Main results
We included two studies (128 participants). Both diabetic neuropathy and non‐diabetic neuropathic pain conditions were investigated across these two studies.
Two herbal medicinal products, namely nutmeg (applied topically as a 125 mL spray for four weeks, containing mace oil 2%, nutmeg oil 14%, methyl salicylate 6%, menthol 6%, coconut oil and alcohol) and St John's wort (taken in capsule form containing 900 μg total hypericin each, taken three times daily, giving a total concentration of 2700 mg for five weeks). Both studies allowed the use of concurrent analgesia.
Both reported at least one pain‐related outcome but we could not carry out meta‐analysis of effectiveness due to heterogeneity between the primary outcomes and could not draw any conclusions of effect. Other outcomes included PGIC, adverse events and withdrawals. There were no data for participant‐reported pain relief of 50% or greater or PGIC (moderate and substantial) outcomes.
When looking at participant‐reported pain relief of 30% or greater over baseline, we observed no evidence of a difference (P = 0.64) in response to nutmeg versus placebo (RR 1.12, 95% confidence interval (CI) 0.69 to 1.85; 48.6% vs 43.2%). We downgraded the evidence for this outcome to very low quality.
We observed no change between placebo and nutmeg treatment when looking at secondary pain outcomes. Visual analogue scale (VAS) scores for pain reduction (0 to 100, where 0 = no pain reduction), were 44 for both nutmeg and placebo with standard deviations of 21.5 and 26.5 respectively. There was no evidence of a difference (P = 0.09 to 0.33) in total pain score in response to St John’s wort compared to placebo, as there was only a reduction of 1 point when looking at median differences in change from baseline on a 0 to 10‐point numeric rating scale.
There was a total of five withdrawals out of 91 participants (5%) in the treatment groups compared to six of 91 (6.5%) in the placebo groups, whilst adverse events were the same for both the treatment and placebo groups.
We judged neither study as having a low risk of bias. We attributed risk of bias to small study size and incomplete outcome data leading to attrition bias. We downgraded the evidence to very low quality for all primary and secondary outcomes reported in this review. We downgraded the quality of the evidence twice due to very serious limitations in study quality (due to small study size and attrition bias) and downgraded a further level due to indirectness as the included studies only measured outcomes at short‐term time points. The results from this review should be treated with scepticism as we have very little confidence in the effect estimate.Authors' conclusions
There was insufficient evidence to determine whether nutmeg or St John's wort has any meaningful efficacy in neuropathic pain conditions.
The quality of the current evidence raises serious uncertainties about the estimates of effect observed, therefore, we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
Adele Boyd, Chris Bleakley, Deirdre A Hurley, Chris Gill, Mary Hannon‐Fletcher, Pamela Bell, Suzanne McDonough
Plain language summary
Herbal products for neuropathic pain
Neuropathic pain is a complex and often disabling condition and many people suffer moderate or severe pain for many years, affecting quality of life. This condition is difficult to treat and typically only 40% to 60% of people with this condition achieve partial relief.
Neuropathic pain is pain coming from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, a fall or cut, or arthritic knee). Neuropathic pain is often treated by different medicines to those used for pain from damaged tissue. Medicines that are sometimes used to treat neuropathic pain can have damaging side effects and therefore people are now trying herbal products to help relieve pain instead.
We conducted a search for relevant clinical trials in March 2018. We looked for studies in adults suffering from moderate neuropathic pain who took some form of herbal product, either by consuming it in their diet, in tablet form, or by applying it to the skin to relieve pain. We also collected information on side effects these herbal products might have.
We included two studies with 128 participants. Study size ranged from 54 to 74 participants with an age range of 21 to 85 years. Both studies included men and women. Both studies compared herbal medicines (nutmeg or St John’s wort) to placebo and allowed continued use of painkillers. Both studies reported side effects.
There were no reports from participants of any reduction in pain intensity of 30% or above and there was no observable reduction in the total pain score in response to either nutmeg or St John’s wort. There were also no reductions in dropout rates or number of side effects between the treatment and placebo.
Quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident.
Only two small studies met this review’s search criteria. Neither provided any high‐quality evidence for either possible benefits or harms. We judged the evidence to be of very low quality. Thus, results from the studies contained in this review are very uncertain and prevent any meaningful conclusions. Larger, high‐quality studies are needed to assess accurately if herbal products are of any benefit or have the potential to harm when used to treat adults with neuropathic pain.
Adele Boyd, Chris Bleakley, Deirdre A Hurley, Chris Gill, Mary Hannon‐Fletcher, Pamela Bell, Suzanne McDonough
Implications for practice For people with neuropathic pain
There was insufficient evidence to suggest that nutmeg or St John's wort has any efficacy in any neuropathic pain conditions. The current evidence is of very low quality resulting in serious uncertainties about the estimates of effect observed. The evidence on adverse events is very low quality and therefore caution should be applied to its usage until more research has been done in this area.For clinicians
There was insufficient evidence to suggest that nutmeg or St John's wort has any efficacy in any neuropathic pain conditions. The current evidence is of very low quality resulting in serious uncertainties about the estimates of effect observed.For policy makers
There was insufficient evidence to suggest that nutmeg or St John's wort has any efficacy in any neuropathic pain conditions and therefore should not be recommended by policy makers at present. Further clinical trials are necessary.For funders
There was insufficient evidence to suggest that nutmeg or St John's wort has any efficacy in any neuropathic pain conditions. The body of the evidence from the two included studies is of too low quality, resulting in serious uncertainties about the estimates of effect observed. Establishing whether these particular herbal products/preparations, or indeed any other herbal product or preparation, have any efficacy would require large clinical trials in several types of neuropathic pain. The evidence surrounding the adverse events associated with current pharmacological treatments for specific types of neuropathic pain and the knowledge that people with this type of pain are likely to try herbal treatments are both justification for further clinical trials investigating the safety and efficacy of herbal medicines in the treatment of such conditions. To ascertain whether pain relief is brought about as a result of nutmeg and St John's wort requires development of the evidence base. This would permit a better assessment of their efficacy and safety.
Implications for research General
Nutmeg and St John's wort have only been investigated in one study each and therefore more studies are required to draw any conclusions on these types of herbal products or preparations. Randomised controlled trials (RCTs) of adequate sample size (i.e. more than 200 participants per treatment arm), duration (longer than 12 weeks), with analysis that does not use imputation methods are required to establish whether herbal medicinal products are effective in reducing neuropathic pain. The two studies that are listed as ongoing (IRCT201201248815N1), or awaiting classification (NCT02107469), will not address this review question any more clearly than those published studies that are reported within this review. The reasons for this are outlined below. We recognise, however, that although further studies would be desirable, it is unlikely that there will be interest to fund these.Design
Studies of cross‐over design with comparison to placebo, no intervention or active comparator and assessing a large study population are required. In addition, studies should be carried out in participants suffering from various types of neuropathic pain and should include long‐term follow‐up assessment of efficacy. Outcome measures should be collected at baseline, at regular meaningful time‐points and at the end of the study. Longer duration studies are required to assess the meaningfulness of any efficacy that might be observed in response to herbal medicinal products. The two studies in this review do not include follow‐up assessment past two months and therefore this highlights the need for further longer‐term studies. Those studies that are ongoing (IRCT201201248815N1), or awaiting classification (NCT02107469), in this area investigate the effects of ajwain cream and Phyllanthus niruri and Sida cordifolia towards neuropathic pain via double‐blind randomised placebo‐controlled trials in participants with neuropathic pain diagnosis as a result of diabetic peripheral polyneuropathy and also postsurgical/post‐traumatic neuropathic pain. These studies did not record outcomes past eight weeks.Measurement (endpoints)
The measurements or outcomes assessed by the studies included in the current review were mostly secondary outcomes that are recommended by IMMPACT, with no data being extracted for primary outcomes aside from 30% pain relief or greater. Future research is needed to investigate these primary outcomes of neuropathic pain management, namely the number of participants obtaining 50% pain relief or greater over baseline, the number of participants obtaining 30% pain relief or greater over baseline, participant‐reported global impression of clinical change (PGIC) much or very much improved (moderate) and participant‐reported global impression of clinical change (PGIC) very much improved (substantial). The ongoing study (IRCT201201248815N1), and study awaiting classification (NCT02107469), also used secondary measures of pain assessment as opposed to those listed as primary outcomes by IMMPACT.Other
Due to the limited number of trials, with few participants, investigating whole plant herbal products/preparations, there is a clear need for large, good‐quality, long‐duration, RCTs in participants suffering from various types of neuropathic pain. These have been done in other chronic conditions (Mills 1996; Oltean 2014), but not of a neuropathic nature. The number of participants investigated in the ongoing study IRCT201201248815N1 and the study awaiting classification, NCT02107469 does not exceed 200 and this, therefore, still poses a high risk of bias, lowering the methodological quality of both studies.
Motilal 2013 was the first clinical trial to be carried out on nutmeg, and therefore further human studies are required on the evidence base, however, the cost of these trials would be at least several million GBP, USD, or EUR. To date, all evidence supporting the analgesic effects of nutmeg has been demonstrated in animal models only (Hayfaa 2013; Sonavane 2001; Zhang 2016).
This review found no high‐quality evidence from good‐quality RCTs to support the use of herbal medicinal products and preparations for neuropathic pain. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Get full text at The Cochrane Library
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