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Combination Therapy for Neuropathic Pain?
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Combined gabapentin and nortriptyline are more effective than either drug given alone for neuropathic pain.
Source: Gilron I, et al. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial. Lancet 2009;374:1252-1261.
Patients with diabetic polyneuropathy or postherpetic neuralgia were randomized to receive one of three sequences of daily oral gabapentin, nortriptyline, and the combination of both drugs in a double-dummy, double-blind, crossover study. Each treatment interval was 6 weeks, and the primary outcome was mean daily pain at maximum tolerated dose. Of the 56 subjects enrolled in the study, 47 completed two treatment periods, and 45 completed all three treatment periods. Mean daily pain (recorded on a 0-10, numerical rating scale) was 5.4 (95% confidence interval [CI], 5.0-5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (95% CI, 2.5-3.8) for gabapentin, 2.9 (95% CI, 2.4-3.4) for nortriptyline, and 2.3 (95% CI, 1.8-2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9; 95% CI, -1.4 to -0.3; P = 0.001) or nortriptyline alone (-0.6; 95% CI, -1.1 to -0.1; P = 0.02). The most common adverse event was dry mouth seen with the nortriptyline and combination treatments.
Nothing causes greater anxiety among Ob/Gyn clinicians than a new patient with chronic pelvic or vulvar pain. I teach our residents that the reason for their discomfort rests in a lack of knowledge of the pathophysiology of these pain disorders and effective treatment strategies. Too often we settle comfortably into our training as surgeons and recommend operative procedures. Our current health care insurance system reinforces this behavior as we are reimbursed much better for doing surgery than we are for office visits.
In my opinion, we focus excessively on the surgical diagnosis and treatment of endometriosis as the leading cause of pelvic pain without strong evidence that this benefits our patients. In a long-term follow-up study of patients with mild-to-moderate endometriosis who had participated in a randomized, double-blind controlled study of laparoscopic laser surgery, pelvic pain had recurred in almost 75% in less than 2 years.1 While some surgeons view this as evidence that repeat surgery is not only necessary but desirable, substantial evidence exists that medical therapy (combined oral contraceptives, GnRH agonists, injectable or implantable progestins, or even the levonorgestrel IUS) offers benefit in terms of pain reduction (principally reduced dysmenorrhea) and disease progression. In fact, a consensus panel concluded that "chronic pelvic pain frequently occurs secondary to nongynecologic conditions that must be considered in the evaluation of affected women. For women in whom endometriosis is the suspected cause of the pain, laparoscopic confirmation of the diagnosis is unnecessary, and a trial of medical therapy, including second-line therapies such as danazol, GnRH agonists, and progestins, is justified provided that there are no other indications for surgery such as the presence of a suspicious adnexal mass."2
I see far too many young women referred for consultation of chronic pelvic pain with a long surgical history. Treated aggressively with surgery for minimal to mild endometriosis, these women undergo repeat surgery every 2 years and peritoneal stripping leads to adnexal adhesions, adnexectomy, and ultimately hysterectomy. Many gynecologists abandon the patient after a pelvic "clean out." Since I see the chronic pelvic pain without pelvic organs, I recognize that a different initial paradigm is needed.
The treatment of pelvic pain requires a multidisciplinary approach. In fact, randomized studies have documented that women treated in a multidisciplinary fashion with psychosocial counseling, medical management for dysmenorrhea, and physical therapy have lower pain scores and much lower rates of surgical intervention than women treated initially with laparoscopy.3 One of the most important and frequently overlooked treatable condition associated with chronic pelvic pain is myofascial pain.4 To treat women with chronic pelvic pain effectively, you need to partner with a physical therapist interested in this problem. Addressing psychosocial stressors and the role of past sexual abuse is also critical, and we serve our patient best when we refer her to a compassionate and well-trained specialist.
As gynecologists, we commonly use narcotics and NSAIDs to manage acute and surgical pain. Prescribing narcotics for chronic pain makes us feel uncomfortable, and represents the principle reason why most of us dislike seeing women with chronic pain. What we often fail to appreciate is the scenarios that bring these women to the emergency room or clinic requesting pain meds. Often the medications are prescribed before and after unneeded surgical procedures. Since narcotics and NSAIDs are ineffective in treating neuropathic pain, dose escalation and iatrogenic narcotic dependence occurs.
Neuropathic pain is transmitted via small nonmyelinated nerve fibers. While the exact mechanisms involved in the etiology of neuropathic pain are incompletely understood, the general features of burning, raw, poorly localized pain without any apparent somatic cause are seen in women with both chronic pelvic and vulvar pain. While there are no large randomized studies of neuromodulators for the treatment of chronic pelvic or vulvar pain, clinicians have extrapolated success from studies of agents used to manage chronic diabetic neuropathic pain or post-herpetic neuralgia. The most widely used drugs include the tricyclic antidepressants (TCAD) and gabapentin. The principle side effect of the TCAD group is dry mouth. Nortriptyline is tolerated better than amitriptyline. Many providers recommend some of the newer, better-tolerated mixed-activity antidepressants like venlafaxine and duloxetine. The SSRIs (fluoxetine, sertraline) don't seem to work as well. Since none of these agents are approved for the treatment of chronic pain, the use is off-label and must be discussed in detail.
I suspect that many of you already are familiar and comfortable with the prescription of SSRIs for depression, and may use lower doses of TCADs for sleep or urge incontinence. While the SSRIs are not effective for pain, I personally have found that venlafaxine or duloxetine are well tolerated in young women and work well in depression and for pain. Gabapentin is an easy drug to prescribe with extremely low systemic toxicity. The principle side effect is dizziness, and this can be avoided by a slow escalation in dose. Limited evidence for the approach of combination therapy with gabapentin and amitriptyline in women with chronic pelvic pain comes from a small randomized study from Germany.5 While we await additional randomized studies of these agents in women with chronic pelvic or vulvar pain, the current report suggests that combination therapy with a TCAD or atypical antidepressant and gabapentin is an important strategy to reduce suffering and narcotic use in women with chronic pelvic pain.