Hamann S, Sloan P.

Department of Anesthesiology, University of Kentucky Medical Center, Lexington, USA.

BACKGROUND: Years’ worth of observations suggest that morphine has both inhibitory and excitatory actions, and that selective blockade of excitatory effects by low doses of opioid antagonists (e.g., naltrexone) may paradoxically enhance morphine analgesia. The purpose of this pilot study was to evaluate and compare the analgesic efficacy and safety of two different low doses of oral naltrexone given in addition to chronic intrathecal morphine infusions in patients with chronic nonmalignant pain (CNMP). METHODS: After institutional review board approval, 15 patients with CNMP receiving continuous intrathecal morphine were admitted into a prospective, randomized, double-blind, placebo-controlled, seven-day pilot study. Patients were randomized into three treatment groups based on oral naltrexone dose: 100 microg (Group A, n = 3), 10 microg (Group B, n = 7), or placebo (Group C, n = 5). All patients continued with their constant intrathecal morphine infusion, and in addition they received one capsule of study medication every 12 hours for seven days. Other analgesics or coanalgesics were kept at a constant dose level throughout the study. Patients rated pain scores (visual analogue score [VAS]; 0 = no pain, 10 = worst pain imaginable) and side effects three times daily throughout the study period. Efficacy measures included pain intensity difference (PID) scores, constructed so that positive scores indicate a reduction in pain intensity and negative scores indicate a worsening of pain. RESULTS: Fifteen patients (six male, nine female) with a mean (SD) age of 55 (10) years and weight of 81 (21) kg completed the study. The mean (SD) baseline VAS pain intensity rating was similar in all three groups (6.8 [1.5]). Baseline pain VAS score minus the lowest daily pain VAS score yielded the peak PID score. The peak PID score from Day 1 was statistically (p < 0.05) highest (median PID score: 5.9) in Group A compared with Group C. There was a trend in PID scores across Days 2 through 7, with median PID scores higher (i.e., greater pain relief p = 0.07) in Group A. In the daily global pain assessments, the pain scores across Days 2 through 7 approached significance (least pain) in Group A compared to Group C (p = 0.07) or B (p = 0.08). Side effects were common (93 percent of patients), minor (headache, nausea, sedation, dry mouth), and similar across treatment groups. No serious adverse events were observed, and no evidence of opioid withdrawal was seen. CONCLUSIONS: 1) Patients with chronic pain who received oral naltrexone 100 microg BID in addition to their chronic intrathecal morphine infusions demonstrated the greatest improvement (p = 0.07) in their daily pain scores. Because of the small sample size, the results did not reach traditional levels of significance. 2) Side effects were common, minor, and similar across treatment groups. 3) No serious adverse events were recorded. 4) No evidence of opioid antagonist toxicity or opioid withdrawal was observed.

Publication Types:

• Research Support, Non-U.S. Gov’t

PMID: 18027539 [PubMed – in process]

Machelska H, Stein C.

Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200, Berlin, Germany. halina.machelska@charite.de

In peripheral inflamed tissue interactions between leukocyte-derived opioid peptides and opioid receptors on sensory neurons lead to potent, clinically relevant inhibition of pain. Opioid receptors are present on peripheral terminals of sensory neurons and are upregulated in inflammation. Their endogenous ligands, opioid peptides, are synthesized in circulating immune cells, which migrate to injured tissues directed by chemokines and adhesion molecules. Under stressful stimuli or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, catecholamines) leukocytes can secrete opioids. These peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur without central opioid side effects such as depression of breathing, clouding of consciousness, or addiction. Future research should elucidate the selective targeting of opioid peptide-containing immune cells to sites of painful tissue injury and the augmentation of opioid peptide and receptor synthesis.

Publication Types:

• Research Support, Non-U.S. Gov’t
• Review

PMID: 18040794 [PubMed – in process]