Can Opioid Tolerance Be Treated by Increasing the Opioid Dose?

Jeffrey Fudin, PharmD


September 01, 2009


A patient has been receiving MS Contin® (controlled-release oral morphine), 60 mg twice daily, for about 22 months. She had excellent pain relief for the first 13 months, but since then has had increasing frequency and severity of breakthrough pain. Does this indicate tolerance? Is it safe to continue increasing the dose?

Response from Jeffrey Fudin, PharmD
Adjunct Associate Professor, Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York; Clinical Pharmacy Specialist, Stratton Veterans Affairs Medical Center, Albany, New York

Tolerance is a physiologic phenomenon described by the American Pain Society as "a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time."[1] "Tachyphylaxis" is the term used when this process happens quickly. Additional explanations for loss of pain control include disease progression, a new or unrelated pain, development or worsening of psychosocial stressors, increased activity, or environmental factors (such as extreme cold or heat).[1,2]

Management of breakthrough pain should begin with evaluating and identifying the source of the pain; then, specific therapies to target that source should be considered. Limited evidence supports the use of immediate-release (or short-acting) opioids for breakthrough or incidental pain beyond a baseline extended-release dosage form. The benefits and potential risks of initiating as-needed opioids should be weighed, and nonopioid or nonpharmacologic alternatives should be considered.[2] Examples of nonpharmacologic alternatives include transcutaneous electrical nerve stimulation, acupuncture, thermal modalities (eg, moist heat), massage, and exercise.[3]

If the benefits of increasing a patient's total daily dose of opioids outweigh the risks, it may be appropriate to increase the dose in order to improve pain control. Risks associated with long-term use of high-dose opioid analgesics (> 200 mg/day) include hyperalgesia, neuroendocrinologic dysfunction, and possibly immunosuppression.[4]Hyperalgesia is the increased response to a stimulus that is normally painful, and it should be suspected when an escalation in opioid dose does not result in adequate analgesia.

Your patient may also benefit from opioid rotation if she does not receive adequate pain relief despite increased opioid doses. Opioid rotation, or switching from one opioid to another, may be an option for patients who do not achieve adequate pain relief with a particular opioid or for patients who experience intolerable adverse effects to a particular opioid.[4]Because of individual variability in response to opioids and incomplete cross-tolerance across opioids, this patient may achieve better pain control when switching opioids rather than increasing the daily dose of MS Contin® or initiating a short-acting as-needed opioid.

If, however, you choose to increase the current regimen of MS Contin®, 60 mg twice daily, specifically because of reported breakthrough pain between doses, the next logical adjustment is to increase the dose and decrease the dosage interval. A reasonable alternative could be oral MS Contin®, 45 mg (use three 15-mg tablets per dose), every 8 hours.

The author wishes to acknowledge Linda J. Tristani, PharmD, Pharmacy Practice Resident, Stratton VA Medical Center, Albany, New York.


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