Friday, June 15, 2012

Depression & Anxiety Hinder Pain Relief

Pain-DepressionIt makes sense that anxiety, depression, and chronic pain often occur together and might influence each other in negative ways. Consequently, a newly-reported trial suggests that the assessment of patient mood, and appropriate treatment for anxiety and/or depression, can be important for maximizing the effectiveness of pain management therapies, such as with opioid analgesics. However, as is often the case, there were limitations of this research that should be taken into account in rating the quality of the evidence.

Patients with chronic noncancer pain frequently report symptoms of depression and anxiety (negative affect), which are associated with higher ratings of pain intensity and a greater likelihood of being prescribed long-term opioid therapy. Writing in an advance online edition of the journal Pain Practice, researchers report a study in patients with low back pain that tested the hypothesis that initial levels of negative affect can predict opioid-treatment-related success in terms of pain intensity, disability, and other variables.

For this study, 459 patients with chronic low back pain had participated in the titration/conversion phase of a multicenter trial, during which they were all administered adequate dosing of once-daily extended-release (ER) hydromorphone. Of these subjects, 268 were then randomized in a double-blind design to either continue receiving ER hydromorphone or were tapered gradually to placebo for 12 weeks. Overall, subjects ranged in age from 18 to 75 years (mean 49 years), 51% were male, 86% Caucasian, and 36% were judged to have neuropathic low back pain.

All patients completed the Hospital Anxiety and Depression Scale (HADS) at baseline and were categorized as having Low, Moderate, and High negative affect based on their scores. Group differences in numerical pain intensity measures, Roland–Morris Disability ratings, and measures of symptoms from the Subjective Opiate Withdrawal Scale (SOWS) throughout the trial were analyzed.

A total of only 110 out of 268 patients (41%) completed this double-blind, placebo-controlled phase of the study. As might be expected, of the 158 who withdrew, 35% was due to lack of efficacy and mostly among placebo group participants. Subjects with Moderate and High negative affect as previously determined by HADS scores tended to drop out more often because of the adverse effects or lack of efficacy of their prescribed medication (opioid or placebo) than those in the Low negative mood group (P < 0.05). Furthermore, patients with Moderate/High negative affect reported significantly higher pain intensity scores (P < 0.05), greater disability on the Roland–Morris Scale (P < 0.01), and more withdrawal symptoms on the SOWS (P < 0.05) than those in the Low group. Higher negative affect scores also predicted less favorable global ratings of the study drug.

The researchers conclude that patients with elevated levels of depression and anxiety are less likely to have positive outcomes when converted to opioid analgesic therapy or are tapered from opioids (the placebo condition in this trial). Patients with Moderate-to-High negative affect appear to experience greater pain and withdrawal symptoms, greater disability, greater dislike of a prescribed opioid during dose titration, and a greater tendency to discontinue therapy than those with lower levels of depression and anxiety.

COMMENTARY: The results of this adequately powered study suggest that the assessment of patient mood — depression and anxiety — can be important for identifying those who might benefit most from opioid therapy. Along with this, when prescribing opioid therapy for persons with chronic pain, diagnosing and treating comorbid mood disorders might considerably improve outcomes.

It is of interest that many of the variables examined in this study did not impact negative affect levels. For example, gender, age, race, objective physical exam findings, and the amount of medication that subjects were taking did not appear to influence HADS scores. One variable that did seem to make a difference was that persons experiencing neuropathic low back pain registered less negative mood, but the authors believe this might have been a random or chance effect.

Low levels of depression/anxiety appear to initially confer greater patient tolerance for adverse effects or discomfort related to ongoing therapy, but these effects may dissipate over time. It is interesting that 44 patients converted to placebo completed the 12-week regimen, compared with 66 receiving opioid therapy and, among these completers, HADS scores between groups were not statistically significant.

Unfortunately, while the authors present a great deal of data in their study report, the data are not portrayed in straightforward ways that aid understanding. Most data are depicted as means and standard deviations with associated P-values, rather than in terms of relative risks or effect sizes and confidence intervals [see discussions of these in our series, “Making Sense of Pain Research” here]. Our own calculations of the latter statistics indicate that, for the most part, differences between the various groups were not robust and effect sizes were small to moderate at best. The significant P-values expressed for differences between groups on various measures merely denote that the outcomes were not due entirely to chance and are not indicative of the strength of evidence or clinical significance.

There also were a number of potentially confounding factors that might have affected outcomes in this study. For example, the researchers concede that patients with increased levels of anxiety/depression might have been concurrently taking psychotropic medications that could have artificially lowered HADS scores. And, it was uncertain how many subjects were receiving psychotherapy for their mood problems. Another limitation was that the study included chronic (> 6 months) but otherwise heterogenous back pain conditions, including pain due to disk disease, arthritis, stenosis, failed back surgery, etc.

Finally, it should be noted that this study was sponsored in part by funding from Mallinckrodt, a Covidien company and manufacturer of ER hydromorphone (Exalgo®), and one of the authors was an employee of the company. Consequently, there might have been some interest in demonstrating that therapeutic failures might be influenced more by individual patient factors rather than the drug itself.

While the findings of this research have important implications for clinical practice and are worthy of consideration, due to the lack of meaningful statistical presentation, the numerous limitations, and potential sources of bias we rate this study and its reporting as relatively low-quality evidence [see a further discussion of evidence ratings in an UPDATE here].

REFERENCE: Jamison RN, Edwards RR, Liu X, et al. Relationship of Negative Affect and Outcome of an Opioid Therapy Trial Among Low Back Pain Patients. Pain Practice. 2012 (Jun 11); online ahead of print [abstract here].

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