Combination pharmacotherapy for the treatment of neuropathic pain in adults
Pharmacotherapy remains an important modality for the treatment of neuropathic pain. However, as monotherapy current drugs are associated with limited efficacy and dose‐related side effects. Combining two or more different drugs may improve analgesic efficacy and, in some situations, reduce overall side effects (e.g. if synergistic interactions allow for dose reductions of combined drugs).
This review evaluated the efficacy, tolerability and safety of various drug combinations for the treatment of neuropathic pain.
We identified randomised controlled trials (RCTs) of various drug combinations for neuropathic pain from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 9 April 2012.
Double‐blind, randomised studies comparing combinations of two or more drugs (systemic or topical) to placebo and/or at least one other comparator for the treatment of neuropathic pain.
Data collection and analysis
Data extracted from each study included: proportion of participants a) reporting ≥ 30% pain reduction from baseline OR ≥ moderate pain relief OR ≥ moderate global improvement; b) dropping out of the trial due to treatment‐emergent adverse effects; c) reporting each specific adverse effect (e.g. sedation, dizziness) of ≥ moderate severity. The primary comparison of interest was between study drug(s) and one or both single‐agent comparators. We combined studies if they evaluated the same drug class combination at roughly similar doses and durations of treatment. We used RevMan 5 to analyse data for binary outcomes.
We identified 21 eligible studies: four (578 participants) evaluated the combination of an opioid with gabapentin or pregabalin; two (77 participants) evaluated an opioid with a tricyclic antidepressant; one (56 participants) of gabapentin and nortriptyline; one (120 participants) of gabapentin and alpha‐lipoic acid, three (90 participants) of fluphenazine with a tricyclic antidepressant; three (90 participants) of an N‐methyl‐D‐aspartate (NMDA) blocker with an agent from a different drug class; five (604 participants) of various topical medications; one (313 participants) of tramadol with acetaminophen; and another one (44 participants) of a cholecystokinin blocker (L‐365,260) with morphine. The majority of combinations evaluated to date involve drugs, each of which share some element of central nervous system (CNS) depression (e.g. sedation, cognitive dysfunction). This aspect of side effect overlap between the combined agents was often reflected in similar or higher dropout rates for the combination and may thus substantially limit the utility of such drug combinations. Meta‐analysis was possible for only one comparison of only one combination, i.e. gabapentin + opioid versus gabapentin alone. This meta‐analysis involving 386 participants from two studies demonstrated modest, yet statistically significant, superiority of a gabapentin + opioid combination over gabapentin alone. However, this combination also produced significantly more frequent side effect‐related trial dropouts compared to gabapentin alone.
Multiple, good‐quality studies demonstrate superior efficacy of two‐drug combinations. However, the number of available studies for any one specific combination, as well as other study factors (e.g. limited trial size and duration), preclude the recommendation of any one specific drug combination for neuropathic pain. Demonstration of combination benefits by several studies together with reports of widespread clinical polypharmacy for neuropathic pain surely provide a rationale for additional future rigorous evaluations. In order to properly identify specific drug combinations which provide superior efficacy and/or safety, we recommend that future neuropathic pain studies of two‐drug combinations include comparisons with placebo and both single‐agent components. Given the apparent adverse impact of combining agents with similar adverse effect profiles (e.g. CNS depression), the anticipated development and availability of non‐sedating neuropathic pain agents could lead to the identification of more favourable analgesic drug combinations in which side effects are not compounded.
Luis Enrique Chaparro, Philip J Wiffen, R Andrew Moore, Ian Gilron
Plain language summary
Drug combinations for chronic neuropathic pain in adults
Neuropathic pain – due to nerve disease or damage – is often treated by pain medications which have limited effect and/or dose‐related side effects when given alone. Combinations of more than one drug are often used with the goal of achieving better pain relief or fewer side effects (if the pain relieving effects of the combined drugs are more additive than the side effects), or both. Despite evidence that over 45% of individuals suffering from neuropathic pain take two or more drugs for their pain, we could find only 21 high‐quality studies of various different systemic and topical drug combinations. Given the wide possible variety of different drug combinations and the small number of studies, results for neuropathic pain from this review are insufficient to suggest the value of any one specific drug combination. However, the publication of multiple high‐quality studies suggesting the superiority of some drug combinations, together with evidence that drug combinations are widely used in clinical practice, underline the importance of conducting more combination studies with improved methodology.
Luis Enrique Chaparro, Philip J Wiffen, R Andrew Moore, Ian Gilron
Implications for practice
Multiple, good‐quality studies demonstrate the superior efficacy of two‐drug combinations. However, the number of available studies for any one specific combination as well as other study factors (e.g. limited trial size and duration) preclude the recommendation of any one specific drug combination for neuropathic pain. Pooled analysis of two studies comparing gabapentin + opioid to gabapentin alone suggested modest analgesic superiority but also reduced tolerability, leaving the overall benefit of this combination unclear. Given that combination pharmacotherapy may increase the risk of toxicity (particularly when the combined drugs produce common adverse effects such as sedation), practical use of analgesic drug combinations requires vigilant risk‐benefit assessment during combination treatment. One common clinical approach to minimising combination toxicity is to use sequential combination therapy, i.e. to start treatment with monotherapy and pursue 'add‐on' combination therapy in cases of partial treatment response. However, this approach may lead to a different dose‐ratio for the combination than might be achieved with simultaneous combination therapy and, possibly, different results (Gilron 2005a).
Implications for research
Demonstration of combination benefits by several individual studies together with reports of widespread clinical polypharmacy for neuropathic pain surely provide a rationale for additional future rigorous evaluations of analgesic drug combinations. Examination of the studies included in this review may serve to guide future improvements in the evaluation of drug combinations for neuropathic pain. It should be noted that, of the 18 included two‐drug combination studies (N.B. one of the 19 studies compared a triple combination to two of its components), only nine compared the combination to both single‐agent components. One problem with this incomplete design is that observed differences between the combination of drugs 'A + B' versus drug 'A' alone could potentially be due strictly to differences in efficacy between drugs 'A' and 'B' and, thus, additional comparison of 'A + B' also with 'B' alone is crucial for the comprehensive evaluation of the combination. Furthermore, nine of the included studies were not placebo‐controlled and five of those failed to demonstrate a difference between the combination of interest and its comparator(s). It should be noted that these five negative studies are essentially inconclusive since, without a demonstrable difference between active treatment and placebo, it is not possible to confirm whether those studies had the assay sensitivity to detect a treatment effect (Dworkin 2010; Max 1991). Therefore, we recommend that future trials of two‐drug combinations include comparisons with placebo and both single‐agent components, as well as reporting outcomes (such as at least 50% pain intensity reduction with tolerable adverse effects) linked to improved functioning over the longer term (at least 12 weeks). In addition to identifying specific drug combinations which provide additional benefit over monotherapy, other objectives to be incorporated into future analgesic combination trials include identification of optimal dose‐ratio for a given combination, cost‐effectiveness comparisons for combination versus monotherapy and the therapeutic benefits of concurrent versus sequential 'add‐on' combination therapy (Gilron 2005a).