COMBINATION THERAPY FOR NEUROPATHIC PAIN

October 1, 2009 — Researchers looking for new ways to treat refractory neuropathic pain suggest that combining gabapentin with nortriptyline may be beneficial. They propose that adding an antidepressant to an anticonvulsant used for pain relief may ease difficult-to-treat neuropathic pain. Exploratory findings were published online September 30 in the Lancet.

"Given the challenges of neuropathic pain, polypharmacy is frequently used," lead investigator Ian Gilron, MD, from Queen's University in Kingston, Ontario, Canada, said during an interview. "But many combinations are not beneficial. We wanted to study this combination in a rational and evidence-based way," Dr. Gilron told Medscape Neurology.

The trial was investigator initiated and was supported by the Canadian Institutes of Health Research. Gabapentin (Neurontin, Pfizer) is a 3-alkylated analogue of γ aminobutyric acid. It was originally developed for the treatment of epilepsy but is widely used as a pain reliever.

Nortriptyline (Pamelor, Novartis) is a metabolite of amitriptyline and reportedly blocks norepinephrine, serotonin uptake, sodium channels, and N-methyl-D-aspartate glutamate receptors.

"This study is most welcome because improved treatment for patients with chronic types of pain is urgently needed," Dr. Troels Jensen and Dr. Nanna Brix Finnerup, from the Aarhus University Hospital in Denmark, said in an accompanying comment.

Neuropathic pain affects an estimated 3% of the general population, and a meta-analysis showed that less than two thirds of patients obtain sufficient pain relief (Pain. 2005;118:289–305).

At the recent American Academy of Pain Medicine annual meeting, experts discussed the challenges of refractory neuropathic pain. Session moderator Perry Fine, MD, from the University of Utah School of Medicine, Salt Lake City, emphasized the limits to what can be accomplished with current therapies.

Challenge of Treating Neuropathic Pain

"Generally, available drugs lack molecular specificity and simply act as antihyperalgesics," Dr. Jensen and Dr. Finnerup add in their article. Drugs that target specific parts of somatosensory processing are now in development and could be used for early treatment before neuroplastic changes have taken place.

However, once chronic pain has set in, with all of its associated biological, psychological, and social effects, Dr. Jensen and Dr. Finnerup suggest that 1 or even 2 drugs that target a specific mechanism are unlikely to cure the patient.

In this double-blind, double-dummy, crossover trial, investigators studied 56 patients. Participants had diabetic polyneuropathy or postherpetic neuralgia and a daily pain score of at least 4 on a scale of zero to 10.

Investigators randomly assigned patients in a 1:1:1 ratio. Participants received 1 of 3 sequences of daily oral gabapentin, nortriptyline, and a combination of both. During each 6-week treatment period, investigators titrated the drugs toward the maximum tolerated dose.

The primary outcome for the trial was mean daily pain at maximum tolerated dose. Analysis was by intention to treat.

Dr. Gilron and his team found that pain with combination therapy was significantly lower than with gabapentin (−0.9; 95% confidence interval [CI], −1.4 to −0.3; P = .001) or nortriptyline (−0.6; 95% CI, −1.1 to −0.1; P = .02) alone.

Pain at Maximum Tolerated Dose

Therapy	Mean Daily Pain	95% CI
Gabapentin	3.2	2.5 – 3.8
Nortriptyline	2.9	2.4 – 3.4
Combination	2.3	1.8 – 2.8

Investigators report no serious adverse events for any patients during the trial. The most common adverse effect was dry mouth, and the participants reported more weight gain in the gabapentin group.

"Combination therapy decreased pain, but it also decreased sleep interference without increasing side effects," Dr. Gilron said. He acknowledged that these promising results will need to be replicated at other centers.

"Gilron and colleagues' trial benefits from being an investigator-initiated study of 2 commonly used drugs for neuropathic pain," note Dr. Jensen and Dr. Finnerup. "This type of study is unfortunately rare because most drug studies are based on large sample sizes from many sites and financed by drug companies."

A drawback of the current study was that the investigators had to keep costs down and thus limited the number of participants. They used a crossover design in which each participant served as his or her own control.

The investigators also provide no data on the benefits of sequential vs simultaneous combination treatment. "In clinical practice, sequential treatment is most common," Dr. Jensen and Dr. Finnerup point out, "but in Gilron and colleagues' study, drugs in combination were given simultaneously."

This study was supported by the Canadian Institutes of Health Research. Lead author Dr. Ian Gilron and senior author Dr. Robyn Houlden have disclosed receiving financial support from Pfizer. Editorialist Dr. Troels Jensen has disclosed that he has received funding from Pfizer, Eli Lilly, and Grünenthal. Editorialist Dr. Nanna Brix Finnerup has disclosed receiving research support from UCB Nordic.

Lancet. Published online September 30, 2009.