Open Access Open Access  Restricted Access Subscription or Fee Access

Tolerability and efficacy of two synergistic ratios of oral morphine and oxycodone combinations versus morphine in patients with chronic noncancer pain

Felix A. de la Iglesia, MD, Gary W. Pace, PhD, Gary L. W. G. Robinson, PhD, Nuo-Yu Huang, MD, PhD, Warren Stern, PhD, Patricia Richards, MD, PhD


Objectives: Analgesic synergy and improved tolerability have been reported for flexible dose morphine and oxycodone combinations. This report describes two studies with similar double-blind, randomized, 7-day crossover designs (up to 7 days per arm) conducted to 1) explore the analgesic and safety benefit of fixed ratio of morphine (M) and oxycodone (O) combinations (MOX) and 2) define the optimal ratio for morphine and oxycodone combination.
Setting: Clinical study centers in Australia.
Patients: Patients with chronic noncancer pain.
Intervention: Eligible patients were randomly assigned to receive flexible doses of either M or fixed ratio of MOX (M3:O2 in study A; M1:O2 in study B). The starting doses of M or MOX were the morphine equivalent doses (MEDs) converted from the analgesics received before entering double-blind treatment. At each crossover period, the doses were titrated to achieve analgesia at steady state, which was defined as when the same total daily dose (±10 percent) had been given consecutively for 3 days.
Main outcome measure: The primary endpoint was the study medication dose (MED), which produced adequate pain control at steady state.
Results: Analgesic synergy in MOX was observed in both studies. On an MED basis, 61.6 percent (study A, M:O = 3:2) or 46.8 percent (study B, M:O = 1:2) more MED were needed for M monotherapy to achieve steady-state pain control when compared with MOX. Patient tolerability profiles were also generally better in the MOX groups.
Conclusion: A 3:2 or1:2 fixed ratio combination of morphine and oxycodone (MOX) produced analgesic synergy and a tolerability profile improvement in patients with chronic noncancer pain.


morphine, oxycodone, analgesia, morphine equivalent dose, adverse events, combination

Full Text:



Blyth FM, March LM, Brnabic AJ, et al.: Chronic pain in Australia: A prevalence study. Pain. 2001; 89(2-3): 127-134.

Elliott AM, Smith BH, Penny KI, et al.: The epidemiology of chronic pain in the community. Lancet. 1999; 354(9186): 1248-1252.

National Center for Health Statistics: Health, United States, 2006 with Chartbook on Trends in the Health of Americans. Hyattsville, MD: Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, 2006.

Chou R: Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: What are the key messages for clinical practice? Pol Arch Med Wewn. 2009; 119: 469-477.

Brennan F, Carr DB, Cousins M: Pain management: A fundamental human right. Anesth Analg. 2007; 105(1): 205-221.

Page GG, Ben-Eliyahu S, Yirmiya R, et al.: Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain. 1993; 54(1): 21-28.

Benyamin R, Trescot AM, Datta S, et al.: Opioid complications and side effects. Pain Physician. 2008; 11(2 Suppl): S105-S120.

Solomon GD: Nonopioid and adjuvant analgesics. In Tollison CD, Satterthwaite JR, Tollison JW (eds.): Practical Pain Management. Philadelphia: Lippincott Williams & Wilkins, 2001: 243-252.

Kehler D, Dahl JB: The value of “multi-modal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993; 77: 1048-1056.

Argoff CE, Silvershein DI: A comparison of long- and shortacting opioids for the treatment of chronic noncancer pain: Tailoring therapy to meet patient needs. Mayo Clin Proc. 2009; 84(7): 602-612.

Trescot AM, Helm S, Hansen H, et al.: Opioids in the management of chronic non-cancer pain: An update of American Society of the Interventional Pain Physicians’ (ASIPP) Guidelines. Pain Physician. 2008; 11(2 Suppl): S5-S62.

Passik SD: Issues in long-term opioid therapy: Unmet needs, risks, and solutions. Mayo Clin Proc. 2009; 84(7): 593-601.

Ross FB, Wallis SC, Smith MT: Co-administration of subantinociceptive doses of oxycodone and morphine produced marked antinociceptive synergy with reduced CNS side-effects in rats. Pain. 2000; 84: 421-428.

Pasternak GW: Molecular insights into mu opioid pharmacology: From the clinic to the bench. Clin J Pain. 2010; 26(Suppl 10): S3-S9.

Blumenthal S, Min K, Marquardt M, et al.: Postoperative intravenous morphine consumption, pain scores, and side effects with perioperative oral controlled-release oxycodone after lumbar discectomy. Anesth Analg. 2007; 105(1): 233-237.

Lauretti GR, Oliveira GM, Pereira NL: Comparison of sustained- release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. 2003; 89(11): 2027-2030.

Mercadante S, Villari P, Ferrera P, et al.: Addition of a second opioid may improve opioid response in cancer pain: Preliminary data. Support Care Cancer. 2004; 12(11): 762-766.

Jamison RN, Raymond SA, Slawsby EA, et al.: Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine. 1998; 23(23): 2591-2600.

Hallenbeck JL: Chapter 4: Pain management: Conversion among different opioids. In Hallenbeck JL (ed.): Palliative Care Perspectives. New York: Oxford University Press, 2003.

Koppitz EM: The Visual Aural Digit Span Test. New York: Grune & Stratton, 1977.

Gaudino EA, Geisler MW, Squires NK: Construct validity in the Trail Making Test: What makes Part B harder? J Clin Exp Neuropsychol. 1995; 17(4): 529-535.

Collins SL, Moore RA, McQuay HJ: The visual analogue pain intensity scale: What is moderate pain in millimetres? Pain. 1997; 72: 95-97.

Aubrun F, Langeron O, Quesnel C, et al.: Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology. 2003; 98: 1415-1421.

Pereira J, Lawlor P, Vigano A, et al.: Equianalgesic dose ratios for opioids. A critical review and proposals for long-term dosing. J Pain Symptom Manag. 2001; 22: 672-687.

Interagency Guideline on Opioid Dosing for Chronic Non- Cancer Pain: An educational aid to improve care and safety with opioid therapy 2010 update. Available at www.agencymeddirectors. Accessed February 2, 2012.

Bolan EA, Tallarida RJ, Pasternak GW: Synergy between mu opioid ligands: Evidence for functional interactions among mu opioid receptor subtypes. J Pharmacol Exp Ther. 2002; 303(2): 557-562.

Simpson K, Leyendecker P, Hopp M: Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-tosevere noncancer pain. Curr Med Res Opin. 2008; 24(12): 3503-3512.

Catala E, Azaro A, Ferrandiz M: Patient affected by severe cancer pain and treated with combined strong opioids. Adv Pain Manag. 2008; 2(2): 76-78.

Ross FB, Smith MT: The intrinsic antinociceptive effects of oxycodone appear to be κ-opioid receptor mediated. Pain. 1997; 73: 151-157.

Pan ZZ: Mu-opposing actions of the kappa-opioid receptor. Trends Pharmacol Sci. 1998; 19(3): 94-98.

Loeser JD: Opiophobia and opiophilia. In Meldrum ML (ed.): Opioids and Pain Relief: A Historical Perspective. Progress in Pain Research and Management. Seattle, WA: IASP Press, 2003: 1-4.



  • There are currently no refbacks.