Rational Opioid Prescribing to Minimize Iatrogenic Addiction

Commentary

Dr. Guay very much appropriately stated in his recent Clinical Geriatrics article titled “Opioid Analgesics for Persistent Pain in the Older Patient:Part I” that true tolerance is a “rare phenomenon,” but that “Prescription opioid abuse in the older population is not a rare phenomenon.”¹ Opioid abuse was not expanded within the context of Dr. Guay’s article in terms of patients with chronic pain who are abusing opioids secondary to iatrogenic addiction as declared by asserting to the myth of tolerance. Readers may benefit from a brief discussion.

Once patients experience euphoria, they seek escalating opioid doses to avoid dysphoria. Assertions of tolerance despite the absence of advancing physioanatomic pathology compels the compassionate clinician to misguidedly escalate dosing rather than tapering opioids and referring the patient for addiction treatment. Clinicians may attribute evolution of addiction purely to genetic predisposition and patient volitional behavior. It is well established that patients with histories remarkable for alcoholism and other risk factors are more susceptible to addiction if opioids are prescribed. It is also undisputed that patients’ foolish decisions to “just try it once” with respect to cocaine, methamphetamine, and heroin (diacetylmorphine) frequently lead to lifelong addiction² with secondary pursuit of prescription opioids to avoid dysphoria, as well as fund the addiction. However, iatrogenic prescribing assumes an important role in the genesis of addiction as related to prescription opioids, such that clinicians have an opportunity to minimize addiction risks while maximizing relief and enhancing function.

Three prescribing patterns potentially initiate addiction and are likened to the mechanisms by which patients become addicted to heroin and tobacco. These mechanisms include rapid onset, cycles of abrupt peak and trough, and high magnitude changes. Heroin and cigarettes precipitate onset of dopamine neurotransmitter spikes in the nucleus accumbens brain pleasure center within seconds.³ Clinicians must understand the enhanced risks associated with rapid-onset opioids characterized by sublingually-delivered agents that bypass the enterohepatic circulation, as these opioids similarly result in presentation of abrupt dopamine surges to the nucleus accumbens, with enhanced risks for iatrogenic addiction. Precipitous peaks and troughs of nucleus accumbens dopamine levels related to short-duration-of-action heroin or nicotine-mediated cigarette use may also induce addiction. As the dopamine levels rapidly decline, the patient craves another spike. This is akin to the abrupt peaks and troughs of short-duration-of-action, dopamine-mediated effects of oxycodone, oxymorphone, hydrocodone, and hydromorphone.

If true long-duration-of-action opioids are preferentially prescribed with a distinct brevity of access to short-duration agents, then the frequency of abrupt peak-and-trough dopamine nucleus accumbens surges and decline is blunted, minimizing iatrogenic addiction risks. This has been empirically supported with respect to short-duration-of-action oxycodone received over a shortened peak and trough period of time having resulted in greater reinforcement behavior relative to slow delivery with a more gradual peak-and-trough,⁴ simulating the lesser risks of reinforcement with 100% long-duration-of-action opioids. Clinical application of these insights has resulted in practitioners having reported successfully minimizing abuse by restricting short-acting medication doses to 60 tabs per month as twice-per-day dosing.⁵ Excessive absolute prescribed magnitude of dose is another risk for iatrogenic addiction. Heroin and cocaine deliver large boluses of dopamine surges to the nucleus accumbens, resulting in addiction.

Clinicians must offer the patient with pain the lowest potentially effective analgesic dose to minimize the amplitude of dopamine surge. As such, preferential initial dosing of a long-lasting opioid should be 10 mg once a day as opposed to 20 or 30 mg twice a day for a given opioid molecule. This strategy minimizes opioid dose-dependent iatrogenic addiction, side effects, and cardiopulmonary toxicities. Reduction of absolute dosing of opioid via pain relief from monitoring and codelivered interventional procedures has been found to diminish abuse by 50%.⁶ This finding is not surprising given animal studies revealing supra-additive potentiation of opioid analgesia by 300% with nonnarcotic local anesthetic delivered to proximity of superficial nerves.⁷ Similarly, morphine equivalent potency must be understood. Strength relative to morphine or buprenorphine up to 40 times potency,⁸ hydromorphone up to 11 times,⁹ and oxymorphone at 10 times the analgesic potency of morphine¹⁰ indicates that these more potent agents should be reserved for pain refractory to lower doses of less potent agents.

A corollary to minimizing iatrogenic addiction related to dosing invokes the inestimable value of patient education. The patient with noncancer pain should be educated to embrace that an acceptable goal should be analogous to the oncology patient, with anticipated increased function concomitant with pain relief down to a 2-4 out of 10 on a 0-10 pain intensity scale.¹¹ Without education, patients may seek higher dosing to achieve a goal of zero pain with iatrogenic euphoria and develop possible addiction disorder, which will manifest as declarations of tolerance when the dysphoria of addiction is perceived as suboptimal pain relief, causing an interminably escalating cascade of solicited dose escalation.

The author reports no relevant financial relationships.

Dr. Geller is Assistant Professor, Tufts University School of Medicine, New England Medical Center, Boston, MA, and President, Nashua Pain Management Corporation.

References

1. Guay DRP. Opioid analgesics for persistent pain in the older patient: Part I. Clinical Geriatrics 2010;18(3):37-46.

2. Hser YI, Evans E, Huang D, et al. Comparing the dynamic course of heroin, cocaine, and methamphetamine use over 10 years. Addict Behav 2008;33(12):1581-1589. Published Online: August 8, 2008.

3. Benowitz NL. Nicotine addiction. N Engl J Med 2010;362(24):2295-2303.

4. Comer SD, Ashworth JB, Sullivan MA, et al. Relationship between rate of infusion and reinforcing strength of oxycodone in humans. J Opioid Manag 2009;5(4):203-212.

5. Jones T, McCoy JD, Moore T, et al. Urine drug testing as an evaluation of risk management strategies. Practical Pain Management 2010;10(5):26-30, 72.

6. Manchikanti L, Manchukonda R, Damron KS, et al. Does adherence monitoring reduce controlled substance abuse in chronic pain patients? Pain Physician 2006;9(1):57-60.

7. Kolesnikov YA, Chereshnev I, Pasternak GW. Analgesic synergy between topical lidocaine and topical opioids. J Pharmacol Exp Ther 2000;295:546-551.

8. Sporer KA. Buprenorphine: A primer for emergency physicians. Ann Emerg Med 2004;43(5):580-584.

9. Trescot AM, Boswell MV, Atluri SL, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician 2006;9:1-39.

10. Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother 2004;18(4):17-30.

11. Sloan PA, Moulin DE, Hays H. A clinical evaluation of transdermal therapeutic system fentanyl for the treatment of cancer pain. J Pain Symptom Manage 1998;16(2):102-111.
___________________________________________________________________________________________________________

Response from David R.P. Guay, PharmD, FCP, FCCP, FASCP

I thank Dr. Geller for his letter sent in response to my two-part series on opioid analgesia in the older patient.^1,2 I agree that iatrogenic addiction is a real—although rare—possibility during opioid therapy of persistent pain, at least in the absence of other concurrent substance abuse disorders. Dr. Geller has reviewed some of the pharmacokinetic factors of drug delivery that are important for the initiation and maintenance of addiction. These have also been reviewed in detail elsewhere.³ It is important to emphasize the rarity of iatrogenic opioid addiction. There have been 25 and five studies, respectively, on the epidemiology of opioid addiction in patients with chronic nonmalignant and chronic malignant pain. However, results have been very difficult to interpret due to differences in the definitions of many terms, the inclusion of other drugs and substances of abuse in the definition of addiction, and the use of inappropriate diagnostic criteria for addiction.

In the seven best-designed studies, only two patients out of 816 (0.25%) were found to have opioid addiction problems.⁴ The neurobiology of opioid addiction is poorly understood. It appears that dopamine does not contribute to the activation of the “pleasure center” in the nucleus accumbens in response to opioids, unlike other drugs of abuse. This is based on the absence of dopamine response, measured by positron emission tomography (PET) brain scans, despite marked subjective and physiological effects after the administration of heroin 50 mg IV and hydromorphone 10 mg SC in 14 heroin addicts on methadone maintenance therapy.⁵ Despite the rarity of iatrogenic opioid addiction in patients with chronic pain, clinicians must monitor for its development. Fortunately, there are some excellent, easy-to-use tools to assist in this. Portenoy⁶ has published a set of criteria for the diagnosis of addiction in the context of patients taking opioids for chronic pain. These criteria are considered superior to those of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria of substance dependence⁷ and those of the International Classification of Diseases (ICD-10) of the World Health Organization.⁸ In addition, Portenoy,⁶ Savage,⁹ and Sees and Clark¹⁰ have developed lists of useful, aberrant drug-related behaviors, patterns, and questions to assist in the evaluation of opioid addiction in patients with chronic pain.

Two excellent, simple screening tools for opioid addiction are available: Screener and Opioid Assessment for Patients with Pain (SOAPP; 2004)¹¹ and the Pain Medication Questionnaire (PMQ; 2004).¹² Is there any way of identifying a priori those patients who will develop opioid addiction during therapy of persistent pain? A recent pilot study was conducted that compared the subjective effects of opioids administered for chronic pain in 20 patients who ultimately developed opioid addiction (cases) to 20 patients who did not develop addiction under close monitoring over a period of years (controls).¹³ The study instrument was the Morphine-Benzedrine Group (MBG) subscale of an adapted version of the 49-item Addiction Research Center Inventory (ARCI). The mean score on the MBG subscale of the ARCI was significantly higher in cases than in controls (8.70 ± 4.18 vs 2.55 ± 1.51, respectively; P £ 0.001), indicating that cases recalled significantly greater euphoric effects from opioids upon initial exposure than did controls. Cases and controls significantly differed in eight of the 46 items (P £ 0.001). However, these eight items reflected five different groups: pentobarbital/chlorpromazine/alcohol group (2 items); benzedrine group (3 items); morphine/benzedrine group (5 items); amphetamine group (2 items); and lysergic acid diethylamide group (2 items). However, the case-versus-control differences were highest in the five items on the MBG subscale. This research group is involved now in a larger study to assess and develop a battery of measures to assist in the prospective identification of patients developing opioid addiction during therapy of chronic pain.¹³

The author reports no relevant financial relationships.

Dr. Guay is Professor of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, and Consultant, HealthPartners Inc., Minneapolis, MN.

References

1. Guay DRP. Opioid analgesics for persistent pain in the older patient: Part I. Clinical Geriatrics 2010;18(3):37-46.

2. Guay DRP. Opioid analgesics for persistent pain in the older patient: Part II. Clinical Geriatrics 2010;18(4):38-47.

3. Nutt D, Lingford-Hughes A. Addiction: The clinical interface. Br J Pharmacol 2008;154:397-405. Published Online: April 14, 2008.

4. Højsted J, Sjøgren P. Addiction to opioids in chronic pain patients: A literature review. Eur J Pain 2007;11:490-518. Published Online: October 27, 2006.

5. Daglish MR, Williams TM, Wilson SJ, et al. Brain dopamine response in human opioid addiction. Br J Psychiatry 2008;193:65-72.

6. Portenoy RK. Chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage 1990;5(1 suppl):S46-S62.

7. American Psychiatric Association, eds. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric Association; 2000.

8. International classification of diseases. World Health Organization. ICD-10:2007. www.who.int/classifications/icd/en. Accessed July 7, 2010.

9. Savage SR. Assessment for addiction in pain-treatment settings. Clin J Pain 2002;18(4 suppl):S28-S38.

10. Sees KL, Clark HW. Opioid use in the treatment of chronic pain: Assessment of addiction. J Pain Symptom Manage 1993;8:257-264.

11. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 2004;112:65-75.

12. Adams LL, Gatchel RJ, Robinson RC, et al. Development of a self-report screening instrument for assessing potential opioid medication misuse in chronic pain patients. J Pain Symptom Manage 2004;27:440-459.

13. Bieber CM, Fernandez K, Borsook D, et al. Retrospective accounts of initial subjective effects of opioids in patients treated for pain who do or do not develop opioid addiction: A pilot case-control study. Exp Clin Psychopharmacol 2008;16:429-434.