Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: A randomized, double-blind, prospective pilot study


  • Scott Hamann, PhD, MD
  • Paul Sloan, MD




chronic pain, opioid agonists, opioid antagonists, intrathecal analgesics, analgesia


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, 15patients 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 gg (Group A, n = 3), 10 gg (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 (leastpain) 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 gg 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.

Author Biographies

Scott Hamann, PhD, MD

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

Paul Sloan, MD

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


Sloan PA, Slatkin NE, Ahdieh H: Effectiveness and safety of oral extended-release oxymorphone for the treatment of cancer pain: A pilot study. Support Ca.re Ca,ncer. 2005; 13(1): 57-65.

Sloan PA, Babul N: Extended-release opioids for the management of chronic non-malignant pain. Expert Opin Drug Deliv. 2006; 3(4): 489-497.

Sloan PA: The evolving role of interventional pain management in oncology. JSupport Oncol. 2004; 2(6): 491-500, 503.

McDonnell FJ, Sloan JW, Hamann SR: Advances in cancer pain management. Curr Oncol Rep. 2000; 2(4): 351-357.

Crain SM, Shen KF: Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons. Trends Pharmacol Sci. 1990; 11(2): 77-81.

Sloan PA, Hamann SR: Ultra-low-dose opioid antagonists to enhance opioid analgesia. J Opioid Manag. 2006; 2(5): 295-304.

Shen KF, Crain SM: Ultra-low doses of naltrexone or etorphine increase morphine’s antinociceptive potency and attenuate tolerance/dependence in mice. Bmin Res. 1997; 757(2): 176-190.

Shen KF, Crain SM: Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Brain Res. 1989; 491(2): 1227-1242.

Kayser V, Guilbaud G: Dose-dependent analgesic and hyperalgesic effects of systemic naloxone in arthritic rats. Brain Res. 1981; 226(1-2): 344-348.

Hamann SR, Martin WR: Hyperalgesic and analgesic actions of morphine, U50-488, naltrexone, and (-)-lobeline in the rat brainstem. Pharmacol Biochem Behav. 1994; 47(1): 197-201.

Crain SM, Shen KF: Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain. 2000; 84(2-3): 121-131.

Hamann SR, Malik H, Sloan JW, et al.: Interactions of “ultralow” doses of naltrexone and morphine in mature and young male and female rats. Receptors Cha-nnels. 2004; 10(2): 73-81.

Levine JD, Gordon NC, Taiwo YO, et al.: Potentiation of pentazocine analgesia by low-dose naloxone. J Clin Invest. 1988; 82(5): 1574-1577.

Cruciani RA, Lussier D, Miller-Saultz D, et al.: Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone. JPain Symptom Manage. 2003; 25(6): 491-500.

Sloan PA, Hodes J, John W: Radiosurgical pituitary ablation for cancer pain. JPalliat Care. 1996; 12(2): 51-53.

Food and Drug Administration (FDA): Guidance for Industry: E6 Good Clinical Practice: Consolidated Guideline. US Department of Health and Human Services. FDA Web site. Available at www.fda.gov/cder/guidance/959fnl.pdf. Accessed April 24, 2007.

Zhou TJ, Tang J, White PF: Propacetamol versus ketorolac for treatment of acute postoperative pain after total hip or knee replacement. Anesth Analg. 2001; 92(6): 1569-1575.

Gimbel JS, Walker D, Ma T, et al.: Efficacy and safety of oxymorphone immediate release for the treatment of mild to moderate pain after ambulatory orthopedic surgery: Results of a randomized, double-blind, placebo-controlled trial. Arch Phys Med Rehabil. 2005; 86(12): 2284-2289.

Fricke JR Jr, Karim R, Jordan D, et al.: A double-blind, singledose comparison of the analgesic efficacy of tramadol/ acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clin Ther. 2002; 24(6): 953-968.

Cousins MJ, Brennan F, Carr DB: Pain relief: A universal human right. Pain. 2004; 112(1-2): 1-4.

Du Pen S, Du Pen A, Hillyer J: Intrathecal hydromorphone for intractable nonmalignant pain: A retrospective study. Pain Med. 2006; 7(1): 10-15.

Levin GZ, Tabor DR: Paraplegia secondary to progressive necrotic myelopathy in a patient with an implanted morphine pump. AmJPhysMedRehabil. 2005; 84(3): 193-196.

Scherens A, Kagel T, Zenz M, et al.: Long-term respiratory depression induced by intrathecal morphine treatment for chronic neuropathic pain. Anesthesiology. 2006; 105(2): 431-433.

Chindalore VL, Craven RA, Yu KP, et al.: Adding ultralowdose naltrexone to oxycodone enhances and prolongs analgesia: A randomized, controlled trial of Oxytrex. J Pain. 2005; 6(6): 392-399.

Webster LR, Butera PG, Moran LV, et al.: Oxytrex minimized physical dependence while providing effective analgesia: A randomized controlled trial in low back pain. J Pain. 2006; 7(12):937-946.




How to Cite

Hamann, PhD, MD, S., and P. Sloan, MD. “Oral Naltrexone to Enhance Analgesia in Patients Receiving Continuous Intrathecal Morphine for Chronic Pain: A Randomized, Double-Blind, Prospective Pilot Study”. Journal of Opioid Management, vol. 3, no. 3, May 2007, pp. 137-44, doi:10.5055/jom.2007.0051.