Chronic Pain

Annotated Abstracts of Journal Articles
2015, 1st Quarter

Chronic Pain

Annotations by Elie Isenberg-Grzeda, MD and Sean Heffernan, MD
March 2015

  1. Out-of-hospital mortality among patients receiving methadone for noncancer pain
  2. Benzodiazepine use among chronic pain patients prescribed opioids: associations with pain, physical and mental health, and health service utilization
  3. The prevalence of pain in bipolar disorder: a systematic review and large-scale meta-analysis

PUBLICATION #1 — Chronic Pain
Out-of-hospital mortality among patients receiving methadone for noncancer pain

Ray WA, Chung CP, Murray KT, Cooper WO, Hall K, Stein CM
JAMA Intern Med 2015; 175(3):420-427

ANNOTATION (Isenberg-Grzeda & Heffernan)

The Finding: The authors used a very large cohort of patients taken from the Tennessee Medicaid records to study the risk of increased mortality among patients prescribed methadone for pain. They found an increased risk of mortality among patients prescribed methadone versus those prescribed morphine. The authors attributed this increased mortality mostly to overdose, and they found this increased risk even among those receiving 20 mg methadone per day.

Strength and Weaknesses: The major strengths were the extremely large sample size of about 68,000 patients, and the well-designed methodological efforts to eliminate bias and confounding as much as possible. For example, they tried to exclude patients with substance abuse and anyone whose cause of death was not attributed to methadone or morphine. Still, the retrospective design is the biggest limitation since it cannot fully eliminate confounding and bias. Also, the use of a state Medicaid registry calls into question the generalizability of the results to other patient populations and settings.

Relevance: This article is extremely relevant to PM/C-L psychiatry. While not listed as one of the aims of the study, the authors found that about two-thirds of patients were receiving benzodiazepines, two-thirds were receiving antidepressants, and about one-sixth were receiving antipsychotics. It is entirely likely that many similar patients will interface with mental health providers. Patients with pain control needs should be counselled accordingly and, when possible, be prescribed safer alternatives to methadone.


Importance: Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias.

Objective: To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate.

Design, Setting, and Participants: A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32?742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients’ median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively.

Main Outcomes and Measures: The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital.

Results: There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P<.001), resulting in 72 (95% CI, 27-130) excess deaths per 10 000 person-years of follow-up. Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P=.046) relative to a comparable dose of morphine SR (<60 mg/d).

Conclusions and Relevance: The increased risk of death observed for patients receiving methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for noncancer pain.

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PUBLICATION #2 — Chronic Pain
Benzodiazepine use among chronic pain patients prescribed opioids: associations with pain, physical and mental health, and health service utilization
Nielsen S, Lintzeris N, Bruno R, Campbell G, Larance B, Hall W, et al
Pain Med 2015; 16(2):356-366

ANNOTATION (Isenberg-Grzeda & Heffernan)

The Finding: This study aimed to characterize the prevalence of benzodiazepine use among patients receiving opioids for chronic noncancer pain. The authors reported that 33% of patients were prescribed benzodiazepines and opioids concurrently, and that while many dosages were within therapeutic norms, most patients did not have one of the few pain diagnoses for which benzodiazepines are indicated. Being a daily benzodiazepine user (about half of all users) was associated with higher opioid doses, greater use of antidepressant and antipsychotic medications, and using recreational drugs.

Strength and Weaknesses: The moderately large sample size and broadly-reaching recruitment efforts are definite strengths of this study. Because this article is the first of what will likely be a series of publications from a larger, parent study, much of the data is preliminary and any inferences must be made cautiously. For example, with data from only one time point, the study design could not determine causality of associations. Also, because the indications for benzodiazepine prescriptions were not recorded, it is difficult to make sound conclusions about their use.

Relevance: The authors identified a high-risk group of patients prescribed benzodiazepines concurrently with opioids, which is a practice that is not recommended in treatment guidelines and debated among experts. While we cannot make inferences about the causality between pain, psychiatric illness, and benzodiazepine use in these patients, the authors bring to our attention a high-risk group that may make their way into PM/C-L practice. I suspect that future articles from this cohort will be worth following.


Objective: Benzodiazepines (BZDs) are commonly used by chronic pain patients, despite limited evidence of any long-term benefits and concerns regarding adverse events and drug interactions, particularly in older patients. This article aims to: describe patterns of BZDs use; the demographic, physical, and mental health correlates of BZD use; and examine if negative health outcomes are associated with BZD use after controlling for confounders.

Subjects: A national sample of 1,220 chronic noncancer pain (CNCP) patients prescribed long-term opioids.

Methods: We report on baseline data from a prospective cohort study comparing four groups based on their current BZD use patterns. General demographics, pain, mental and physical comorbidity, and health service utilization were examined.

Results: One-third (N?=?398, 33%) of participants reported BZD use in the past month, and 17% (N?=?212) reported daily BZD use. BZD use was associated with: 1) greater pain severity, pain interference with life, and lower feelings of self-efficacy with respect to their pain; 2) being prescribed “higher-risk” (>200?mg oral morphine equivalent) doses of opioids; 3) using antidepressant and/or antipsychotic medications; 4) substance use (including more illicit and injection drug use, alcohol use disorder, and daily nicotine use); and 5) greater mental health comorbidity. After controlling for differences in demographic characteristics, physical and mental health, substance use, and opioid dose, BZD use was independently associated with greater past-month use of emergency health care such as ambulance or accident and emergency services.

Conclusions: CNCP patients using BZDs daily represent a high-risk group with multiple comorbid mental health conditions and higher rates of emergency health care use. The high prevalence of BZD use is inconsistent with guidelines for the management of CNCP or chronic mental health conditions.

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PUBLICATION #3 — Chronic Pain
The prevalence of pain in bipolar disorder: a systematic review and large-scale meta-analysis
Stubbs B, Eggermont L, Mitchell AJ, De Hert M, Correll CU, Soundy A, et al
Acta Psychiatr Scand 2015; 131(2):75-88

ANNOTATION (Isenberg-Grzeda & Heffernan)

The Finding: Using a systematic review of the literature and meta-analysis, the authors compiled a sample of 171,352 patients with bipolar disorder (BD) and 12,204,292 controls. They concluded that nearly 30% of BD patients report pain, which is about double the prevalence of healthy controls. Not uncommonly, BD patients also reported chronic pain and migraines.

Strength and Weaknesses: The study’s search methodology is considered the gold standard in systematic reviews, and they obtained an incredibly large sample size. The main weaknesses are that the data came from cross-sectional studies; BD patients are a heterogenous group whose illness characteristics were not reported; and pain assessments varied widely and were mostly not validated measures. As such, this study could not report on key information, such as which phase of bipolar illness respondents were in at the time of assessment or whether or not pain varied over time.

Relevance: It is commonly understood that depression and pain often co-exist, but the same cannot be said of pain and BD until now. This is the first systematic review and metaanalysis of pain and BD, which, given the high prevalence of comorbidity, is concerning. Pain can negatively impact BD in several ways including hindering recovery and increasing suicide risk, and the authors are correct in suggesting that psychiatrists routinely assess BD patients for pain. Given that medications frequently used for pain (e.g., TCAs, NSAIDS) may carry higher risks in patients with BD, it is possible that there may be a role for PM/C-L psychiatrists in helping manage the treatment complexities of this patient population.


Objective: To conduct a meta-analysis investigating the prevalence of pain in people with bipolar disorder (BD).

Method: A systematic review and random effects meta-analysis searching major electronic databases from inception till 01/2014 in accordance with the PRISMA statement. We included articles reporting quantitative data on the prevalence of pain in people with BD with or without a healthy control group. Two independent authors conducted searches, extracted data, and completed methodological quality assessment.

Results: Twenty two cross-sectional studies were included, representing 12,375,644 individuals (BD n=171,352, n controls=12,204,292). The prevalence of pain in people with BD was 28.9% (95% CI=16.4-43.4%, BD n=171,352). The relative risk (RR) of pain in BD compared to controls was 2.14 (95% CI=1.67-2.75%, n=12,342,577). The prevalence of migraine was 14.2% (95% CI=10.6-18.3%, BD n=127,905), and the RR was 3.30 (95% CI=2.27-4.80%, n=6,732,220).About 23.7% (95% CI=13.1-36.3%, n=106,214) of people with BD experienced chronic pain. Age, percentage of males, methodological quality, and method of BD classification did not explain the observed heterogeneity.

Conclusion: People with BD experience significantly increased levels of pain (particularly chronic pain and migraine). The assessment and treatment of pain should form an integral part of the management of BD.

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