Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 13th World Congress on Pain

Montreal, Quebec / August 29-September 3, 2010

Pain is often a symptom that serves as a warning signal of some underlying disease process. Treatment is consequently directed towards identification and resolution of the primary disease pathology. However, as argued here at the WCP by Dr. Michael Cousins, Chair, Executive Committee for the Australian National Pain Strategy, there is ample evidence to support the concept that persistent or chronic pain is a disease in its own right. Studies have demonstrated that in the setting of chronic pain, there are persistent altered peripheral inputs as well as persistent dorsal root ganglion and spinal cord changes which are pathophysiological.

There is also increasing evidence showing persistent thalamic, limbic system and cortical neuroplasticity changes in chronic pain. As Dr. Cousins noted in an article co-authored with Siddall (Anesth Analg 2004;99:510-20), the changes that occur in the setting of chronic pain can be traced all the way from the periphery to the brain, and these changes are manifested as specific signs and symptoms indicative of pathology at these various levels. “Pain ultimately is caused by primary pathology,” the authors state.

The presence of pain for any length of time results in consequences that make up the secondary pathology of pain. This is dependent not only on nociceptive inputs but also largely determined by the person’s environment, including mood changes and central sensitization. For example, neuropathic pain likely involves central sensitization after damage to peripheral sensory nerves. At the same time, it should be recognized that mood changes including anxiety and depression alter both perception of pain and its expression.

“When you put all these together, whatever the disease the patient had to start with, they now have a second disease and that disease deserves to be treated,” Dr. Cousins emphasized.

Psychological and Social Factors

Thinking about chronic pain as a disease entity means not to limit treatment to symptom management but to deal with the primary pathology as well as possible, and to identify the secondary pathology or consequences of the pain (including environmental factors) that contribute to pain maintenance.

Here at the WCP, as discussed by Kenneth Craig, PhD, Professor Emeritus of Psychology, University of British Columbia, Vancouver, physicians need to consider psychological and social factors that are associated with chronic pain. “Addressing psychosocial factors complements biomedical assessment and intervention and is necessary to ensure comprehensive care,” he noted. For example, early identification of excessive emotional reactions to pain—anxiety, depression, destruction thinking, catastrophizing, helplessness—can help patients begin the process of adjusting to their pain.

Deteriorating social relationships and increasing social isolation reinforces pain perception, therefore patients need to learn good coping skills and accept that pain may not be eliminated. “Only if we utilize comprehensive psychosocial models will we begin to understand the complexities of our patients’ lives and deliver effective care,” Dr. Craig told delegates.

Treatment of Neuropathic Pain

Harriet Wittink, PhD, Professor in Lifestyle and Health Research Studies, Utrecht University of Applied Sciences, The Netherlands, concurred that patients with chronic pain in general, and diabetic peripheral neuropathic pain (DPNP) in particular, mostly care about the impact that pain has on their ability to function. Patient-reported outcomes offer valuable insights in this regard. A review (Neurology 2007;68:1178-82) indicated that neuropathic pain is highly detrimental to many health-related quality-of-life (HRQoL) domains including physical, emotional and social functioning. Sleep interference is also common in patients with DPNP and various studies report that in these patients, as many as 35% experience moderate to severe anxiety while almost 30% also report depression.

Among agents widely used to treat neuropathic pain are tricyclic antidepressants (TCAs). While effective in many cases, they do have the potential for important adverse events (AEs). As a commonly-used TCA for the treatment of neuropathic pain, amitriptyline is poorly tolerated in older patients mainly because of its anticholinergic effects.

From a mechanistic standpoint, both serotonin and norepinephrine in the brain and the spinal cord are believed to regulate pain perception and mediate core mood symptoms. Thus, blockade of the reuptake of both serotonin and norepinephrine will increase the activity of both neurotransmitters in the brain, helping regulate both pain and mood. As an effective selective serotonin-norepinephrine reuptake inhibitor (SSNRI), duloxetine is currently indicated for the treatment of DPNP.

In a study comparing duloxetine to amitriptyline in patients with DPNP, Hota et al. reported that at the end of 6 weeks, pain relief following optimal titration of the SSNRI was good in 49% of patients compared to 35% of those on the TCA, although there were no significant differences between the 2 groups in either the McGill pain questionnaire or the Likert pain scale. Of some 33 AEs reported at study end point, 79% were associated with amitriptyline use and 33% with duloxetine. With fewer and milder AEs, investigators concluded that duloxetine might be a suitable alternative to amitriptyline in DPNP.

In a pooled analysis of 12-week data involving over 1100 DPNP patients (Pain Med 2007;8:410-8), duloxetine 60 mg q.d. or b.i.d. was compared to placebo. Patient-reported functional outcomes were measured using several questionnaires including the Short Form 36 (SF-36) and interference portion of the Brief Pain Inventory (BPI).

As assessed by both the SF-36 and the BPI interference, both doses were significantly superior to placebo in all domains including mood, sleep and general activity levels. “When pain changes enough to affect outcomes such as sleep and function, you have done a good job at treating that pain,” Dr. Wittink observed.

Dr. Cousins cited pooled data from the same studies showing that the mean change in average pain severity at study end point was significantly better for both duloxetine doses than that reported with placebo (P<0.05). The probability of response (defined as a =50% reduction in pain from baseline) was again greater for both doses of the duloxetine than for placebo.

Fibromyalgia

For treating fibromyalgia (FM), Dr. Cousins told delegates that it is similar to DPNP “in that multi-modality treatments appear to be very reasonable in light of currently available options.” As in DPNP, HRQoL scores indicate that the impact of FM on functional outcomes may be worse than other diseases including systemic lupus or rheumatoid arthritis.

In one of two studies evaluating duloxetine in FM cited by Dr. Cousins (Pain 2005;119:5-15), 354 female patients with FM with or without major depressive disorders received 12 weeks of duloxetine 60 mg q.d. or b.i.d. or placebo. At study end, patients on active doses had significantly greater improvements in BPI pain severity and interference scores, Fibromyalgia Impact questionnaire, Clinical Global Impression of Severity and several QoL measures compared with placebo.

In the second study (Arthritis Rheum 2004;50:2974-84), 207 FM patients received duloxetine 60 mg b.i.d. or placebo. At the end of 12 weeks, decreases in both average pain severity and interference due to pain were both significantly greater for those on active therapy vs. placebo, as were improvements in several QoL measures.

Both DPNP and FM have also been shown to respond well to the anticonvulsant pregabalin. In a study by Richter et al. (J Pain 2005;6:253-60), 246 patients with DPNP were treated with either pregabalin 150 or 600 mg or placebo for 6 weeks. The higher dose of pregabalin significantly reduced mean pain scores at the end of treatment to 4.3 vs. 5.6 for placebo as well as increased the proportion of patients who had =50% decrease in baseline pain to 39% vs. 15% for placebo.

In FM, Crofford et al. (Arthritis Rheum 2005;52:1264-73) treated 529 patients with 1 of 3 doses of pregabalin or placebo for 8 weeks. At study end, pregabalin 450 mg/day significantly reduced the average severity of pain compared with placebo and significantly more patients had at least a 50% improvement in pain (29% vs. 13% for placebo) along with improvement in several HRQoL measures, including sleep and fatigue.

Summary

Chronic pain such as DPNP and FM is among the most costly of disease states from a societal standpoint and one that deserves a concerted effort to assess and manage effectively. Unlike other agents, duloxetine has dual capabilities to modulate pain and mood. Frequently, anxiety and depression are concurrent in chronic pain states. A single agent that can address both conditions may streamline treatment and obviate concerns about addiction, another important consideration in the treatment of chronic pain states such as DPNP and FM.