Writing in the February 2011 edition of the Journal of Pain researchers from the David Geffen School of Medicine at UCLA, Los Angeles, investigated the effectiveness of a conservative, hold-the-line (Stable Dose) opioid analgesic prescribing strategy compared with a more liberal dose titration approach (Escalating Dose) [Naliboff et al. 2011]. Using a prospective, parallel-group, randomized design, this clinical trial followed 135 patients for 12 months after referral to a specialty pain clinic at a local Veterans Affairs (VA) Healthcare System hospital.
Participants were 94% male, mean age 52 years, and 74% had chronic musculoskeletal pain of ≥6-months duration. All had already been using opioid medications for pain (roughly 30 mg/day morphine equivalents on average) at the time of enrollment and still had average usual pain levels of about 7 on a 10-point scale.
All subjects received identical pain treatment, including adjunctive medications, except for the application of treatment group specific strategies for opioid prescriptions. Primary outcomes included monthly or quarterly evaluations of pain severity, pain relief from opioid medication, pain-related functional disability, and opioid misuse behaviors.
While the Escalating Dose group had a small but significantly greater increase in self-rated pain relief from opioid medication, there were no other significant group differences for primary outcomes of usual pain or functional disability. About 27% of patients overall were discharged during the course of the study due to opioid misuse/noncompliance, but there were no differences between groups in rates of opioid misuse/abuse or other substance abuse.
COMMENTARY & CAVEATS: Opioids have no ceiling limit in terms of analgesic effectiveness and liberal prescribing practices may facilitate more adequate pain relief; however, there have been ongoing concerns about the need to limit dose escalation to control tolerance, side effects, and opioid misuse/abuse. The authors of this present study conclude that their Escalating Dose strategy facilitated improvements in self-reported acute pain relief without any corresponding increases in opioid misuse.
While this appears to allay concerns about problematic opioid-use behaviors automatically occurring with more liberal opioid dosing, there also are some severe limitations of this research that must be considered:
- The authors describe their approach as a “pragmatic trial” that simulates a real-world clinical environment, with simple inclusion criteria, a flexible treatment protocol, and a heterogenous population. However, if anything, the study population appears to be a homogenous group of persons at high risk for opioid misuse or abuse at the outset. For example:
- Subjects comprised an almost exclusively middle-aged, male VA population;
- Many patients were included with a prior history of substance abuse disorder (but not within 2 years of enrollment in the study). Nearly half of participants (47%) had a history of substance misuse excluding alcohol, 65% had past alcohol abuse problems, and 40% had both alcohol and other substance related disorders 2 or more years prior to enrollment [disparities in these data adding up to more than 100% were unexplained];
- Furthermore, 24% of participants had current depression, 22% had an anxiety disorder, and 25% met criteria for current post traumatic stress disorder.
- In view of this uniquely high-risk population it is all the more remarkable that liberal prescribing of opioids did not incur greater rates of substance abuse and medication noncompliance. While a third (33%) of subjects in the Stable Dose group were dropped from the study due to opioid or clinical noncompliance only 26% of those in the Escalating Dose group exhibited such violations (a noteworthy but statistically nonsignificant difference between groups). Furthermore, 10% of all discontinuations were due to illicit substance abuse, but this included marijuana.
- Patients in the Stable Dose group were allowed opioid dose increases only when deemed medically necessary; whereas, those in the Escalating Dose group were given moderate dose increases when reporting inadequate pain relief, including possibly switching from a short-acting to long-acting formulation. However, it took 7 months for there to be significant dosing differences of any size between groups, so it is not surprising that most discontinuations due to substance misuse/abuse (60%) occurred during the first 6 months. Yet, by the end of the 12-month study there was only a 17 mg/day morphine-equivalents difference in dosing levels between the two groups.
- Patients in the Escalating Dose group experienced 21% more pain relief compared with only 2% in the Stable Dose group. However, the amount of such relief was not dramatic, considering that only 28% of those receiving more liberal doses achieved greater than a 1.5 point improvement in pain on a 10-point visual analog scale.
- The researchers report that they did not monitor the occurrence of opioid side effects (eg, nausea, headache, somnolence, or constipation). This is a serious deficiency of the study, since adverse reactions can be prime reasons for limiting dose titration; however, this apparently was not a factor hindering attainment of more rapid and or higher “adequate dosing” in the Escalating Dose group.
In short, this study is disappointing in that it was not a true test of unrestricted, liberal opioid-dose titrations to achieve adequate pain relief. And, this insufficiency appeared to be driven by policy rather than clinical necessity, since the investigators did not even track adverse opioid effects that might have otherwise limited dose-increase timing or ceilings.
Despite the above limitations, which are of great concern, the study does suggest that increasing opioid doses to achieve greater pain relief does not automatically result in corresponding increases in opioid misuse and abuse, even among patients at high risk of such problems. However, until better research is conducted, having clear distinctions between conservative and liberal dosing conditions, and in more typical patient populations, it would be presumptuous to propose other conclusions from this study.
REFERENCE: Naliboff BD, Wu SM, Schieffer B, et al. A Randomized Trial of 2 Prescription Strategies for Opioid Treatment of Chronic Nonmalignant Pain. J Pain. 2011;12(2):288-296 [abstract here].