Study Shows Changes in Dosing During Long-term Opioid Therapy Have Little Effect on Pain Score

In “Lack of Correlation Between Opioid Dose Adjustment and Pain Score Change in Chronic Pain,”¹ their study on opioid dose adjustment and pain score change in a group of chronic pain patients, published in The Journal of Pain, Chen et al used Spearman correlation coefficient analysis to demonstrate that changes in opioid dosing and clinical pain score were not correlated in a subset of chronic pain patients over a prolonged course of opioid therapy. These non-significant results remained even after adjustments for chronic pain type, gender and age.

The study consisted of a retrospective analysis of patients enrolled in the Research Patient Database Registry (RPDR), on opioid medications identified at more than two visits at the Massachusetts General Hospital Center for Pain Medicine dated from January 2001 to December 2007, as well as review of physician schedules for more recent visits.

In total, 927 charts were identified. The final analysis consisted of 109 charts based on the following criteria:

• Patients with nonmalignant chronic pain conditions
• Patients on opioid medication(s) during three or more office visits
• Clinical charts containing information on opioid medication, opioid dose, clinical pain condition, medical history, other medications, and clinical pain score

The participant’s initial and ultimate opioid dose and pain scores were recorded during a seven-year period. The total follow-up time was, on average, 704 days. Subjects were divided into three subgroups based on the difference in opioid dose between the initial and last visits: at least 20% increase, 20% decrease, and no change (defined as less than 20% change from the initial visit).

There was no correlation between overall opioid dose and clinical pain score point change across all 109 subjects (R2 = .0027; P > .05; 95% confidence interval [CI], 6.11 to 6.89). In the opioid dose increase subgroup (49/109; 45%), there was no overall correlation between opioid dose increase and clinical pain score point change (R2 = .0248; P > .05; 95% CI, -8.30 to 3.90). In the opioid dose decrease subgroup (36/109; 33%), there was no overall correlation between opioid dose decrease and clinical pain score point change (R2 = .0052; P > .05; 95% CI, -12.12 to 1.92).

These results suggest that opioid dose increase and decrease did not significantly alter clinical pain score over the course of opioid therapy in these subjects. Twenty-four subjects (24/109; 22%) experienced no overall opioid dose change. In this subgroup, the overall correlation was not provided. Results suggested that clinical pain score varied over the course of opioid therapy even in the absence of opioid dose change.

There was no correlation between changes in opioid dose and clinical pain score for subjects with neuropathic pain (R2 = .0045; P > .05; 95% CI, -4.57 to 7.17), nociceptive pain (R2 = .0044; P > .05; 95% CI, -16.22 to _0.58); mixed pain conditions (R2 = .0005; P > .05; 95% CI, -11.29 to 3.09). There were no statistical differences in the percent point change of the clinical pain score, nor were there differences between male and female subjects, among all three age groups (<40; 40-60; >60) in response to opioid dose change.

Chen et al also examined whether the opioid dose at the initial visit would influence the effectiveness of chronic opioid therapy. The 109 subjects were divided into low dose (<75 mg) versus high dose (>75 mg) groups based on their daily morphine equivalent dose at the initial visit. The results suggested that opioid dose at initial visits had little influence on clinical pain score at the last visit during a course of chronic opioid therapy.

Commentary from Dr. Kalira

Despite the widespread use of opioids in patients with chronic pain, the lack of randomized controlled trials is not surprising given the complexity of chronic pain. In addition, when trials are conducted, study participants often lack comorbidities that further complicate effective treatment in the real world and limit generalizability of results. There has been a relative increase in research on long-term opioid therapy; however, its effectiveness in chronic pain remains elusive and is addressed primarily in review articles.

Noble et al² reviewed 26 studies with 27 treatment groups that enrolled a total of 4,893 participants. Overall, they concluded that there is weak evidence that oral opioids reduce pain for the long-term in patients with chronic non-cancer pain. However, they state that proper management of opioids in carefully-selected patients without a history of substance addiction or abuse can lead to long-term pain relief for some patients with a very small risk of developing addiction, abuse, or other serious side effects.

Trescot et al³ reported that, for long-term opioid therapy of six months or longer in managing chronic non-cancer pain with improvement in function and reduction in pain, there is weak evidence for morphine and transdermal fentanyl and limited evidence for all other opioids including the most commonly used ones, oxycodone and hydrocodone.

Manchikanti et al⁴ conducted a comprehensive review on long-term opioid therapy on chronic pain patients and found weak evidence for pain relief and associated improvement in functional status. In addition, Martell et al⁵ reported that long-term use of 16 weeks or longer of opioids was ineffective for chronic low back pain in their systematic review.

The current literature does not provide enough evidence to guide the prescription of opioids in long-term management. Overall, the evidence base for the effectiveness of opioids in chronic noncancer pain management is sparse, providing only weak evidence to show that opioid pain medications are effective for chronic noncancer pain in some patients for months to years. The limitations of a systematic review invite the use of alternative approaches of study.

Portenoy et al⁶ conducted an open-label, multi-site, uncontrolled prospective longitudinal investigation of opioid pharmacotherapy for chronic noncancer pain. Patients used controlled-release oxycodone for up to 36 months to control chronic pain. They completed the Brief Pain Inventory at each three-month return visit. Of the 233 patients enrolled, 39 completed the study. Of those who remained, scores for worst pain decreased from 7.7 (± 1.6) at baseline to 5.4 (± 2.5) at the end of month three and remained relatively stable over the study’s duration. Despite limitations, this study demonstrates that at least a subgroup of patients with chronic noncancer pain can reap long-term benefits from opioid pharmacotherapy without complications.

The retrospective analysis of Chen et al¹ focuses on the lack of significant changes in pain score despite changes in opioid dose in chronic pain patients on a prolonged course of opioid therapy (an average of 704 days). These findings are consistent with the overall literature. The differences observed in individual trials reinforce the need to individualize therapy based on clinical effectiveness for that patient in order to optimize the treatment outcome.

Vicki Kalira, MD, is a psychiatry resident at Johns Hopkins Hospital.

References:

1. Chen L, Vo T, Seefeld L, Malarick C, Houghton M, Ahmed S, Zhang Y, Cohen A, Retamozo C, St. Hilaire K, Zhang V, Mao J. Lack of Correlation Between Opioid Dose Adjustment and Pain Score Change in a Group of Chronic Pain Patients. The Journal of Pain, Vol 14, No 4 (April), 2013: pp 384-392.

2. Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010 CD006605.

3. Trescot AM, Helm S, Hansen H, Benyamin R, Adlaka R, Patel S, Manchikanti L. Opioids in the management of chronic non-cancer pain: An update of American Society of Interventional Pain Physicians’ (ASIPP) guidelines. Pain Physician 2008; 11:S5-S62.

4. Manchikanti L, Vallejo R, Manchikanti KN, Benyamin RM, Datta S, Christo PJ. Effectiveness of Long-Term Opioid Therapy for Chronic Non-Cancer Pain. Pain Physician 2011; 14:E133-E156

5. Martell BA, O’Connor PG, Kerns RD, Beck WC, Morales KH, Kosten TR, Fiellen DA. Systematic review: Opioid treatment for chronic back pain: Prevalence, efficacy, and association with addiction. Ann Intern Med 2007; 146:116-127.

6. Portenoy RK, Farrar JT, Backonja MM, Cleeland CS, Yang K, Friedman M, et al. Long-term use of controlled-release oxycodone for noncancer pain: results of a 3-year registry study. Clin J Pain. 2007;23:287—299.