Abstract

Background

Clonidine is a presynaptic alpha‐2‐adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015.

Objectives

The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain.

Search methods

For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021.

Selection criteria

We included randomised, double‐blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain.

Data collection and analysis

Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information.

We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta‐analyses. We used a fixed‐effect model if we considered heterogeneity as not important; otherwise, we used a random‐effects model. 

The review primary outcomes were: participant‐reported pain relief of 50% or greater; participant‐reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow‐up period.

We assessed the certainty of evidence using GRADE and created two summary of findings tables.

Main results

We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double‐blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double‐blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias.

TC compared to placebo

There was no evidence of a difference in number of participants with participant‐reported pain relief of 50% or greater during longest follow‐up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant‐reported pain relief of 30% or greater during longest follow‐up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow‐up period (12 weeks) or very much improved on PGIC during the longest follow‐up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow‐up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow‐up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence). 

TC compared to active comparator

There was no evidence of a difference in the number of participants with participant‐reported pain relief of 50% or greater during longest follow‐up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported.

Authors' conclusions

This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC.

Author(s)

Wojciech T Serednicki, Anna Wrzosek, Jaroslaw Woron, Jaroslaw Garlicki, Jan Dobrogowski, Joanna Jakowicka-Wordliczek, Jerzy Wordliczek, Renata Zajaczkowska

Abstract

Plain language summary

Clonidine applied to the skin for adults with chronic neuropathic pain

Key message

We found no high certainty evidence to support the use of clonidine applied to the skin for painful diabetic neuropathy. We found no evidence for other chronic pain conditions.

What did we do?

To find out how clonidine applied to the skin (topical clonidine) works in people with neuropathic pain, we searched medical databases and references of retrieved papers and registries or clinical trials. We also contacted experts in the field. Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. When necessary, we contacted trial authors to request additional information.

What did we find?

We identified four studies for inclusion in the review. The studies lasted 8 weeks to 85 days and included a total of 743 participants with painful diabetic neuropathy. Clonidine (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily, and was compared with placebo (dummy treatment) in three studies and with capsaicin applied to the skin in one study.

Limitations in how the studies were conducted and reported and the small amount of evidence available means that our confidence in the results is limited. The evidence suggests that in adults with painful diabetic neuropathy, topical clonidine may provide pain relief in some people. However, topical clonidine was not better than placebo for our other outcomes. We found no evidence of a difference between topical clonidine and capsaicin applied to the skin in painful diabetic neuropathy. The information from clinical trials is not enough to judge about possible long‐term side effects of clonidine applied to the skin; however, we found that during 8 to 12 weeks of treatment there was no evidence of a difference in number of side effects between study groups. We also do not know from the included trials how clonidine works in other chronic neuropathic pain conditions.

How up‐to‐date is this evidence?

The review is current to 27 October 2021.

Author(s)

Wojciech T Serednicki, Anna Wrzosek, Jaroslaw Woron, Jaroslaw Garlicki, Jan Dobrogowski, Joanna Jakowicka-Wordliczek, Jerzy Wordliczek, Renata Zajaczkowska

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For adults with chronic neuropathic pain

The major implication of this review for people with chronic neuropathic pain is that a higher percentage of adults with painful diabetic neuropathy (PDN) may achieve pain relief of 30% or greater when treated with topical clonidine (TC) compared with placebo (48% versus 36%); however, the evidence for this outcome is very uncertain. Eight more people would have to be treated with TC compared to placebo for one more person to achieve moderate benefit. We found no evidence on how TC works in people with other neuropathic pain conditions.

For clinicians

The major implication of this review for clinicians is that TC may provide some benefit to adults with PDN; however, the available evidence is very uncertain. The percentage of participants who achieved pain relief of 50% or greater was comparable to that in placebo group, although the percentage of participants who achieved pain relief of 30% or greater was higher in the TC group compared with the placebo group (48% versus 36%). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was over 8, which means that eight more people would have to be treated with TC compared to placebo for one more person to achieve moderate benefit. Other drugs are available for treatment of individuals with PDN with lower NNTB; however, there may be circumstances when an experienced clinician may choose to use it, because the evidence does not exclude beneficial effects in a small percentage of people, especially in situations where other available therapies have failed or as part of multimodal approach to refractive pain syndromes. We found no evidence on how TC works in people with other neuropathic pain conditions.

Some clinicians may be concerned about long‐term safety of the drug and would prefer to see more safety data. There were no differences in numbers of participants with adverse events, numbers of withdrawals due to adverse events or lack of efficacy, and overall withdrawal rate between TC and placebo; however, it is possible that differences may not have been detected due to the relatively low number of included participants and relatively short duration of the trials. As only a very small concentration of clonidine is reached in plasma during topical application (Campbell 2012), it can be assumed that topical use will be associated with rather few important adverse events, although this is not certain.

Another difficulty is that a ready‐to‐use preparation of TC is not currently available, and the drug for topical use has to be prepared by a compounding pharmacy. Moreover, TC does not have US Food and Drug Administration or European Medicines Agency approval for neuropathic pain and thus must be prescribed 'off‐label'. 

For policymakers and funders of the intervention

TC may provide some benefit to adults with PDN; however, the available evidence is of very low certainty. The circumstances in which this therapy would be tried are likely only when other available treatment options have failed, or as part of a multimodal approach to refractive pain syndromes. Lack of data precludes any conclusions on the effectiveness of TC in other neuropathic pain conditions.

Implications for research 

General implications

This review has highlighted the lack of good evidence for TC for neuropathic pain treatment. We found very low quality evidence suggesting that TC may provide some benefit to adults with PDN, although only about one out of eight people treated with the drug may achieve pain relief of 30% or greater when compared with placebo. Chronic neuropathic pain is difficult to treat, and even effective pharmaceuticals provide relief to only a minority of people. Future research might thus explore whether it is possible to predict who or which groups of people with PDN will benefit from TC. 

Additionally, good‐quality clinical trials are needed to establish the role of TC in other neuropathic pain conditions such as postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, complex regional pain syndrome, and others. 

The treatment period of the studies included in this review was 8 to 12 weeks. Longer duration trials would be more appropriate to establish the efficacy of TC in chronic pain conditions. Moreover, trials of longer duration are needed to assess the safety of TC. Extension studies from randomised controlled trials could provide some additional evidence. 

Design

The optimal future clinical trial to answer the review question should last 3 months or longer, include a minimum of 400 participants, and have a randomised, double‐blind, placebo‐controlled or parallel‐group design. Proper randomisation method, allocation concealment, and blinding of participants and personnel should be guaranteed. Detection bias should be minimised by the blinding of outcome assessment. Missing data should be managed with last observation carried forward or another reliable imputation method. Presentation of results should be clear. Non‐pharmaceutical industry‐sponsored trials would be preferred whenever possible. 

Measurement (endpoints)

Future research should include outcome measures that are relevant to clinical practice. The gold standard for now is the 'responder' analysis, although this has recently been questioned (Mbowe 2020). It might thus be reasonable to present additional 'mean values' analysis to better reflect the real‐life situation. 

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