1. 2013;16;E85-E94Pharmacovigilance: A Review of Opioid-Induced Respiratory Depression in Chronic Pain Patients
   Comprehensive Review
   Albert Dahan, MD, PhD, Frank Overdyk, MD, Terry Smith, PhD, Leon Aarts, MD, PhD, and Marieke Niesters, MD.

BACKGROUND: Opioids may induce life-threatening respiratory depression, but limited knowledge is available on factors that contribute to opioid-induced respiratory depression (OIRD). This is especially true for patients with chronic pain on prolonged opioid therapy. There are no good quality case control studies or randomized controlled trials available on this topic. Here we present and analyze all case series since 1980 on OIRD in chronic pain patients extracted from PubMed.

OBJECTIVE: To describe and understand clinically identified factors involved in life-threatening OIRD in patients receiving opioids for chronic pain relief.

STUDY DESIGN: A literature search was performed for all relevant case reports on OIRD in chronic pain.

METHODS: We searched PubMed (www.ncbi.nlm.nih.gov) for all available case reports/series on OIRD in adolescent (12 years and older) and adult patients treated with opioids for chronic pain, from which we identified specific commonalities that contributed to OIRD (akin to closed claims analyses). The dataset was post-hoc divided into 2 distinct categories: cases published from 1980 to 1999 and those from 2000 to 2012.

RESULTS: Thirty-four reports describing 42 chronic pain patients experiencing OIRD were retrieved. Cases published before the year 2000 (pre-2000) predominantly involved morphine in cancer patients, whereas cases since 2000 (post-2000) predominantly involved methadone or transdermal fentanyl in non-cancer pain patients. Specific factors that contributed to OIRD were elevated opioid plasma levels due to renal impairment and sensory deafferentiation in pre-2000 cases, and elevated plasma levels due to drug interactions on the cytochrome P450 in post-2000 cases.

LIMITATIONS: The case series analysis of published case reports imposes limitations in terms of the types of cases presented (only severe cases are published or cases with specific precipitating factors), the journal-related publication strategy, and changes in clinical practice.

CONCLUSIONS: Our case review confirms that life-threatening OIRD in chronic pain patients involves a series of complex often-interacting factors. In spite of the factors identified in this cases series, OIRD remains unpredictable and safe opioid prescribing requires careful titration of opioid dosages and continuous monitoring to prevent life-threatening OIRD.