title: Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers.
abstract: Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.
authors.affiliation: UCSF Pain Clinical Research Center, Department of Neurology, University of San Francisco, CA, USA Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Karin Lottrup
authors.initials: KL
authors.lastname: Petersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Meadoff
authors.forename: Scott
authors.initials: S
authors.lastname: Press
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Peters
authors.forename: Matthew D
authors.initials: MD
authors.lastname: LeComte
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rowbotham
mesh_terms: D000328:Adult; D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D009619:Nociceptors / Q000187:drug effects / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D015990:Placebo Effect; D010919:Placebos; D012016:Reference Values; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D010919:Placebos; D009020:Morphine