Combination Pharmacotherapy for Neuropathic Pain: Is it Better than Monotherapy?

The review included 40 double blinded, randomized controlled studies (4741 participants) on the use of combination pharmacotherapy.

A Note on Opioids: Although the efficacy of opioids for the management of neuropathic pain is questionable and these medications are not generally considered first line treatments for this type of pain, the study found that many of the combination studies included opioids.

Opioids Combined with a Gabapentinoid: In 4 studies where treatment was initiated with an opioid to which a gabapentinoid—either gabapentin or pregabalin—was added there was no difference found in pain relief between the opioid monotherapy and the combination. In 2 studies in which an opioid was added to initial gabapentinoid monotherapy a moderate/good improvement in pain was found.

Opioids Combined with a Gabapentinoid (adverse events/drop out rate): These studies found an increase in significant adverse events with the opioid-gabapentinoid combination compared to monotherapy including dizziness, fatigue, and somnolence. When a gabapentinoid was added to an opioid, there was no significant increase in study drop out rates related to adverse events. However, when an opioid was added to a gabapentinoid, the drop out rate increased to 14.5% compared to the 4.6% drop out rate when the gabapentinoid was used alone.

Opioid Combined with an Antidepressant: The studies found no difference in pain relief either with adding an antidepressant to an opioid or adding an opioid to an antidepressant. Curiously, there were fewer study dropouts because of adverse events when the antidepressant was added to the opioid than when the opioid was used alone, but there were fewer dropouts for the antidepressant monotherapy than when an opioid was added.

Ketamine Combined with Another Analgesic: The ketamine-gabapentin and the ketamine-calcitonin combinations provided more pain relief than gabapentin or calcitonin alone. However, ketamine combined with the other medications offered no more relief than these medications alone. The ketamine-gabapentin combination caused a significantly higher number of reports of dizziness compared to gabapentin monotherapy; the ketamine-methadone combination resulted in severalsignificant adverse events, such as nausea, vomiting, and constipation.

Combinations of Topical Analgesics: None of the combinations appeared to offer any more pain relief than the use of the single agents alone. As would be expected with topical analgesics, adverse events were rare and minor when they occurred in both the combination and monotherapy groups.

Combinations Using Other Medications: The results were at bestmixed and none of the combinations appeared to be clearly superior to any of the monotherapies while there was often a marked increase in adverse events with combination therapies.

Meta-analysis Conclusions: Although combinations of medications for the management of neuropathic pain appear to be frequently used in clinical practice, there is currently no research that provides any firm support for the approach. There are only a limited number of studies, many with a relatively small number of subjects, that have examined combination therapies and the methodology utilized in them varies. Even where there are indications that a combination may be more efficacious, most notably combining a gabapentinoid-antidepressant, there are only a small number of studies to support the practice.

Meta-analysis Conclusions: There was also a great deal of variance between studies regarding the duration of treatment with the various agents. In some it was as little as a week while in others it was several months. In some studies subjects were allowed to use other analgesics in addition to those being studied. Virtually all the studies examined only pain levels to measure response to treatments without evaluating level of function which is considered of greater importance when studying responses to therapies for chronic pain.

Important Caveats to Consider: 1. Because the 3 most commonly utilized classes of medications that were reviewed—antidepressants, gabapentinoids, and opioids—all exert their effects on the central nervous system resulting in similar adverse events, when combinations of these medications are used the doses of each often need to be reduced below those considered optimal analgesic doses of the individual medications, which may offset any benefits that may be provided by the additional medication.