importance of opioid tolerance

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PALLIATIVE CARE

The Importance of Opioid Tolerance:A Therapeutic Paradox

A Reed Thompson, MD, FACS, James B Ray, Pharm D

Surgeons appreciate that a responsibility to manage painis an integral part of their practice. Multiple treatmentmodalities for optimally managing pain are frequentlynecessary, but knowledgeable use of analgesic drugs isthe most essential because drug therapy is the mainstayof pain treatment. The most important analgesic druggroup to understand is the opioids. Opioids are potent,versatile, and safe (except for meperidine and propoxy-phene, which have toxic metabolites), but they are fre-quently underused in patients with chronic pain, such as

cancer patients, who are commonly seen in a surgicalpractice.

Physicians are aware of the dangers of opioid use,particularly respiratory depression, but many have anincomplete understanding of the safety of opioids, par-ticularly with longterm use. This leads to underprescrib-ing and to inadequate pain relief. The safety of opioids isrelated to two unique pharmacologic properties and tothe development of tolerance.

Unique properties of opioids

Opioid analgesics have two unique pharmacologic prop-erties that are not thoroughly appreciated. These twoproperties are at the core of their safety as analgesics.

Opioids do not damage organs

Opioids at any dose do not cause visceral organ damage.1

This cannot be said of any other analgesic drug group.Salicylates and other nonsteriodal antiinflammatorydrugs (NSAIDs) can cause irreversible renal damage athigh doses.2 Acetaminophen can cause irreversible he-patic and (rarely) renal damage at doses greater than4,000 mg/day.3 The dose-limiting factor in opioid use isnot the risk of organ damage, but the development ofintractable side effects, such as nausea, vomiting, som-

nolence, myoclonus, and cognitive failure, all of whichare reversible with dose reductions or rotation to alter-native opioids or use of adjuvant medications. There is arecent report describing hypogonadism in patients onlongterm opioids.4

Opioids do not have a ceiling dose

The pharmacologic ceiling refers to a plateau on adrugs dose-response curve beyond which additionaldose increases produce no change in efficacy and only

cause more side effects or toxicities;5

it is a propertycommon to most pharmacologic agents. There is noplateau on the opioid dose-response curve, so there is noceiling for opioids. Increases in an opioid dose mostoften advance drug efficacy, and increased analgesia isproduced with each dose escalation.

There is pain that cannot be controlled with doseincreases because of the persistence of moderate to severeopioid-related side effects. This has been termed painthat is poorly responsive to the opioid. This is relatedto mechanisms that can increase the potential for side

effects such as metabolite accumulation and tolerance.6-9

These two propertiesthe lack of organ toxicitiesand lack of a ceilingmean the development of toler-ance to the analgesic effect of opioids is clinically irrele-vant. An opioid dose can always be increased withoutconcern about the total number of milligrams pre-scribed, and an increase in analgesia will be realized. Theappropriate dose of an opioid is that which is required tocontrol the pain.

Opioid tolerance

Pharmacologically, tolerance is defined as loss of drugeffect with chronic dosing.10 The mechanism of opioidtolerance is partially understood in mammals.11 Toler-ance is a complex receptor-selective phenomenon. Theglutamatergic receptor (GluR) system has been impli-cated in the development and maintenance of morphinetolerance; this in part mediated byN-methyl-D-aspar-tate (NMDA) receptors. Some common intracellularpathways are shared between pathologic pain states andopioid tolerance.12-15

No competing interests declared.

Received November 7, 2002; Accepted November 7, 2002.From the Palliative Care Service, University of Arkansas for Medical Sciences,Little Rock, AR (Thompson), and the Department of Pharmacy, HamotMedical Center, Erie, PA (Ray).Correspondence address: A Reed Thompson, MD, FACS, University of Ar-kansas for Medical Sciences, Slot 748, 4301 Markham St, Little Rock, AR72205.

321 2003 by the American College of Surgeons ISSN 1072-7515/03/$21.00

Published by Elsevier Science Inc. PII S1072-7515(02)01800-8


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Development of tolerance to the analgesic effect ofopioids with chronic use is widely known, and it is gen-erally believed to be a negative aspect of opioid use be-cause dose requirements to maintain analgesia must in-crease over time. But development of tolerance to opioid

side effects, which also occurs with chronic use, is lesswell appreciated.16 Development of tolerance to opioidside effects is the other aspect of opioid pharmacologythat contributes to opioid safety.

Tolerance to the analgesic effect of opioids can beginafter a few weeks of around-the-clock dosing, as doestolerance to the respiratory depression effect of opioids(and other side effects except constipation). As tolerancedevelops, side effects usually resolve, and the respiratorydepression effect of opioids disappears. Tolerant patientscan receive steadily higher opioid doses without risk of

respiratory depression as long as the dose increases areappropriate (25% to 50% increase with each doseescalation).

Clinical significance of opioid tolerance

Respiratory depression is the most feared complicationof opioid therapy. It can be seen in opioid-naive patients(those who are not opioid tolerant) as doses are esca-lated. Symptomatic respiratory depression with dose es-calation is very unusual in patients on chronic opioidtherapy because tolerance to the respiratory depressioneffect develops. Concern about causing a dangerous re-spiratory depression with chronic opioid use is generallyunwarranted and can prevent adequate pain relief. Thisconcern should not prevent aggressive opioid use in sur-gical patients with chronic pain. Even if a symptomaticrespiratory depression occurs during opioid therapy, thepatient can often be observed, but if necessary, it can bereversed with dose reduction, and if needed, the judi-cious use of an opioid antagonist.

The following case report illustrates the safety of opi-oid therapy in a tolerant patient.

MK was a 56-year-old man who presented with ab-dominal pain, obstructive jaundice, and a mass in thehead of his pancreas on abdominal CT scan. Therewas no evidence of liver involvement, and the masswas believed to be potentially resectable. But at thetime of laparotomy the mass was found to be invad-ing the portal vein and was determined to be unre-sectable. The biliary system and stomach were by-passed for palliation. MK opted for a trial of

chemotherapy, but it was discontinued because thetumor responded poorly.

The jaundice cleared, but the surgery and chemother-apy did not notably reduce his pain. He had constant,dull, midabdominal pain without descriptors suggestiveof a neuropathic component. Initially, he was placed onoral extended-release morphine around the clock plusimmediate-release morphine as needed for break-through pain. This controlled his pain well, but over thenext few months his morphine requirement slowly in-creased as his disease advanced. The only opioid sideeffect he experienced was constipation, which was man-aged with stimulant laxatives. He was able to stay athome and eventually opted for hospice care. He did not

want cardiopulmonary resuscitation.Months later he still had constant midabdominal pain

with occasional sharp exacerbations. He was taking 300mg of oral extended-release morphine every 8 hours plus50 mg of oral immediate release morphine 4 to 5 timesper day for breakthrough pain. He developed ascites,peripheral edema, dyspnea, and his functional status haddeclined dramatically. He developed problems swallow-ing his medicines, and his morphine was changed to theIV route through his existing infusaport. Over the nextfew months, his IV morphine dose was escalatedsteadily. Each dose escalation relieved the pain for only

few weeks. He was seen by a pain consultant for a pos-sible celiac plexus block, but the block was not believedto be feasible. At 18 months after operation he was on IVmorphine 100 mg/hour plus 25 mg boluses every 10minutes as needed for breakthrough pain. He continuedto complain that he had severe, and at times unbear-able, abdominal pain. He was seen by a psychiatricconsultant who recommended an antidepressant, butthe consultant found no evidence of substance abusebehavior.

Over the ensuing weeks the morphine was increased

steadily. After another 6 weeks the patient was receiving500 mg/hour morphine IV plus 60 mg IV boluses every10 minutes as needed. He was bed-bound, alert withoutconfusion, and his pain was moderately well controlled.There was no evidence of respiratory depression; respi-rations were 10 per minute. The next dose escalation wasto 800 mg/hour of morphine IV plus 75 mg IV bolusesevery 10 minutes as needed. He was maintained on thisdose for 3 weeks without developing notable opioid sideeffects, such as sedation.

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The final dose escalation was to 1,100 mg/hour ofmorphine IV plus 100 mg IV every 10 minutes asneeded. MK lived 3 days on this morphine dose. He wassomnolent his last day, but he could be aroused to takefluids with gentle verbal stimulation. He had mild my-

oclonus. His respirations were 8 per minute withoutevidence of cyanosis. He died quietly at home.

Opioid tolerance is a good thing

The case of MK illustrates the points made above regard-ing the safety of opioid analgesics, morphine in this in-stance, when the doses are increased appropriately. MKreceived an incredibly high daily dose of intravenousmorphine without serious complications. He was ren-dered pain-free in his last days. He died at home, as was

his wish and he died without undue suffering. The safetyof opioid analgesics made this possible. He was keptpain-free but not at the cost of marked respiratory de-pression or other opioid side effects.

Physicians generally believe that opioid tolerance is abad thing because increasing opioid doses are required tomaintain analgesia. Although tolerance to the analgesiceffects of opioids can present a challenge to providingpain relief, the same capacity of developing tolerance toother opioid effects such as sedation and respiratory de-pression make the phenomenon of tolerance generally

advantageous in the clinical setting. In many instances,the reason for an increasing opioid requirement clearlycorrelates with the progression of underlying disease.Fortunately, if either tolerance to the analgesic effect orthe progression of disease is the reason for increasingopioid requirements, the dose can be safely increasedbecause of tolerance to other opioid effects, as was donein this case. Other therapeutic approaches such as opioidrotation,17,18 coanalgesics,19 ketamine,20,21 and axial de-livery22 should be considered in situations where escala-tion of the opioid dose is not effective. A dose escalationmight not be effective if it is impractical, too costly, orassociated with undesirable side effects, such as can oc-cur in cases of unrecognized neuropathic pain or whenopioid dose requirements continue to increase becauseof development of tolerance to the analgesic effect.

Appreciation of the positive aspects of opioid toler-ance and understanding the conditions that mimic it canmake a large contribution toward reduction of sufferingin surgical patients.

Appendix

Surgical Palliative Care Workgroup

Geoffrey P Dunn, MD, FACS, Erie, PA, Series EditorPeter Angelos, MD, PhD, Chicago, ILPatrice G Blair, MPH, Chicago, IL

Karen Brasel, MD, FACS, Milwaukee, WITimothy G Buchman, PhD, MD, St Louis, MOSusan Jo Bumagin, MEd, Gloucester, MAIra Byock, MD, Missoula, MT

John L Cameron, MD, FACS, Baltimore, MDJoseph M Civetta, MD, FACS, Farmington, CTAlexandra M Easson, MD, FRCS(C), Toronto, OntarioDaniel B Hinshaw, MD, FACS, Ann Arbor, MI

Joan L Huffman, MD, FACS, Upland, PAWendy C Husser, MA, MPA, Chicago, ILDennis L Johnson, MD, Hershey, PA

Olga Jonasson, MD, FACS, Chicago, ILThomas J Krizek, MD, FACS, Wesley Chapel, FLRobert S Krouse, MD, Tucson, AZK Francis Lee, MD, FACS, Springfield, MALaurence E McCahill, MD, FACS, Alhambra, CARobert A Milch, MD, FACS, Buffalo, NY

Anne C Mosenthal, MD, FACS, Newark, NJGretchen Purcell, MD, PhD, Durham, NC

Ajit Sachdeva, MD, FACS, Chicago, ILA Reed Thompson, MD, FACS, Little Rock, ARDavid Weissman, MD, FACP, Milwaukee, WI

H Brownell Wheeler, MD, FACS, Worcester, MA

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