THERAPEUTIC USE OF CONTROLLED SUBSTANCES
From Pain Management and End-of-Life Care: A Comprehensive Approach to Patient Care, presented by the University of
California, San Diego, Schools of Medicine, Nursing, and Pharmacy
| RATIONAL USE OF OPIOIDS IN MANAGING PAIN —Scott Fishman, MD, Professor of Anesthesiology and Pain
Management, and Chief, Division of Pain Medicine, University of California, Davis, School of Medicine
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| “Damned if you do and damned if you don’t”: physicians often criticized (or even sued) by public for not treating pain
adequately, while simultaneously being accused by regulatory agencies of overprescribing opioids, thus contributing
to drug abuse and addiction; speaker opines that what public and legal system really want is evidence that physicians
care about suffering and are willing to do something to relieve it
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| Definitions: drug addiction—compulsive use of drug that causes dysfunction, and continued use despite that dysfunction;
pseudoaddiction—seeking relief from pain when pain undertreated; pseudoaddict’s behavior may mimic that
of addict, but when drug administered, pseudoaddict’s function improves while addict’s function deteriorates;
tolerance—effect of drug decreases over time, requiring more and more drug to achieve same effect; physical
dependence—withdrawal reaction occurs when drug discontinued abruptly; some drugs (eg, clonidine) cause physical
dependence without addiction and some (eg, cocaine) cause addiction without physical dependence
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| Selecting patients: functional outcome most important consideration; ask patient what he or she wants to do on opioid
that he or she cannot do now; if patient says, “nothing,” opioid probably not necessary, suggest drug with less risk;
if answer unrealistic (eg,“be a guard for the Lakers”), negotiate for more realistic goal; keep list of desired functional
outcomes and review it periodically to determine whether function improving; “bottom line is that when
we prescribe drugs that can have side effects minimize the risk as much as possible”; educate self and patient
about side effects and watch for them assiduously
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| Avoiding side effects: addiction most worrisome, and “physicians have a responsibility to minimize the potential for
abuse and diversion”; perform complete evaluation, including obtaining history and doing physical examination,
reviewing patient’s medical records, and collecting collateral information; refer patient to specialist when necessary;
provide best treatment possible and follow up vigorously; document everything thoroughly
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| Opioids: many different agents available; given by “every route known to mankind” (eg, orally, intramuscularly, transdermally);
some now available in long-acting and sustained-release forms; some intrinsically long acting, some
more intermediate in action
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| Methadone: has properties other than opioid effect, including being N-methyl-D-aspartate (NMDA) antagonist and
serotonin reuptake inhibitor with possible analgesic properties; used for maintenance because of optimal half-life
for euphoric effect ( ≥1 day; analgesic half-life 4 to 8 hr); equianalgesic tables wrong (developed >20 yr ago, based
on single-dose studies in normal subjects or in people in acute pain; do not account for effects of long-term use),
can lead to overdose in opioid-naive person; biometabolism intrinsically unstable (uses different P450 enzyme than
other opioids and interacts differently with other drugs); bound to protein, and levels can change suddenly in unstable
patients; 40% excreted in urine
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| Pain: generally categorized as persistent pain or breakthrough pain; with persistent pain, particularly chronic pain, long-
acting opioid preferable; with breakthrough pain, agent (usually short-acting opioid) that can be tailored to pain
spikes works better
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| Goals for treatment: improved level of independent function; increase in activities of daily living; decreased pain
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| Discontinuation: not inappropriate if goals not being met; for example, patient may report pain relieved but function
not improving; side effects may impair patients’ ability “to get on with their lives”; some patients may become hyperalgesic
because of opioids
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| Adherence: clinician must be vigilant; strategies for improving adherence include having patient sign opioid contract,
obtaining permission to test patient’s urine, obtaining permission to review patient’s records, and asking patient to
agree to use just one pharmacy; in California, Controlled Substance Utilization Review Evaluation System
(CURES) data already available, should be available elsewhere in near future
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| Contracts: “anything that’s bilaterally agreed upon in the course of treatment is a contract,” no matter what label it
has (even verbal contracts have been upheld by courts); some contracts elaborate and detailed (even running to 40
pages), but average <3 pages; survey found that most contracts include descriptions and expectations of care,
consequences of problems, procedures for discontinuation, education, administrative issues, and terms of compliance
monitoring, but some contain much more “and have very frightening terms in them”; great variability
found in contracts from different providers; efficacy of contracts not established; no record of physician suing patient
for breach of contract, but many patients have successfully sued physicians for same, so “if you’re going to
use contracts make sure that you follow your own terms”
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 | Effect of contract on patient: patient may find contract demeaning or insulting; patient may think clinician believes
patient untrustworthy; may make patient untrusting (like “they’re [being] lied to”); patients may even become
paranoid and delusional if contract not worded carefully; take care that contract does not sound pejorative or paternalistic
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| Effect of contract on clinician: may engender false sense of safety, ie, that patient’s signing contract assures adherence
to it; “well, it doesn’t; you’ve got to continue to be vigilant”
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| Other things about contracts: can be used as guideline if problems arise; can be referred to if either party forgets his
or her responsibilities; formalizes process of educating patient and obtaining informed consent, and may predispose
patient to succeed; speaker’s institution implemented getting patient’s primary care physician involved in
contract process and found primary care physicians more than willing to participate; speaker suspects that patients
who did not discuss contract with primary care physicians most likely to be troublesome later
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| Conclusions: many opioid drugs available, but opioid should not be only drug given for pain; rather, should be part of
balanced treatment plan; use short- and long-acting opioids judiciously; determine if pain persistent or breakthrough
and prescribe opioids accordingly; remain vigilant for side effects and abuse; aim for functional improvement
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| THE USE OF MARIJUANA IN PAIN AND PALLIATIVE CARE —Donald I. Abrams, MD, Professor of Clinical
Medicine, University of California, San Francisco, School of Medicine, and Chief, Hematology/Oncology, San Francisco
General Hospital
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| Brief history of medicinal use of cannabis: first used probably in China ≈5000 yr ago, then spread to India; introduced
in United States and United Kingdom in 1840s; subject to many regulations, many of which discouraged research
into its medicinal properties; in United States, classified as schedule I substance (substances with no accepted medical
use) in 1970; since then, “every 10 years a government agency requests another investigation into the medicinal
use of marijuana; every 10 years the same conclusions are reached and every 10 years they are ignored” (1999
Institute of Medicine report said that cannabis has probable utility for treatment of pain, nausea, vomiting, and loss
of appetite, and [guess what?] it was ignored); 1996 California legislation suggested marijuana useful in treatment
of cancer, anorexia, AIDS, spasticity, glaucoma, arthritis, migraine, and any other illness for which it provides relief
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| Chemistry of marijuana: plant contains >400 compounds; Ä9-tetrahydrocannabinol (Ä9-THC) primary active ingredient,
and highest concentration found in resin exuded from flowers of female plant; at least 60 other cannabinoids
also found in plant, any or all of which may enhance beneficial effects of Ä9-THC, possibly explaining why
smoked marijuana more efficacious than dronabinol (Marinol; pharmaceutical preparation of Ä9-THC); cannabinoids
are group of 21-carbon terpenophenolic compounds uniquely produced by marijuana plant
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| Endocannabinoids: humans and other mammals produce endocannabinoids; CB1 and CB2 cannabinoid receptors coupled
to proteins and inhibit adenylate cyclase; CB1 receptors found in brain, and activation inhibits N-type voltage-gated calcium
channels, increases potassium conductance in hippocampal neurons, and increases prostaglandin production; CB1
receptor thought to be involved in control of appetite, immune function, emesis, muscle control, pain, reward, and thermoregulation;
CB2 receptors not found in brain, but in macrophages and marginal zone of spleen, suggesting role in immunity;
studies ongoing to learn how to manipulate endocannabinoid system for pharmacologic and physiologic effect;
many drug companies concentrating research on creating receptor antagonist
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| Symptoms of cancer that might respond to cannabinoids: weight loss; cachexia; early satiety; anorexia; pain; nausea
and vomiting; anxiety and depression
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| Cannabis: first approved in 1986 for control of chemotherapy-induced nausea and vomiting; indications expanded in
1996 to include treatment of anorexia-induced weight loss
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| Pharmacology of oral THC: bioavailability low and variable; peak plasma concentration occurs 2.5 hr after ingestion,
and terminal half-life 20 to 30 hr; Ä9-THC metabolized by liver to psychoactive 11-hydroxy metabolite
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| Pharmacology of smoked THC: rapidly absorbed into bloodstream and redistributed; considerable amount of dose
lost in smoke and destroyed by pyrolysis; peak blood level occurs at end of smoking, with rapid decline over next
30 min; smoking achieves higher peak concentration but shorter duration of effect, and smaller amount of psychoactive
11-hydroxy metabolite formed
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| Cannabinoids and pain: elevated numbers of CB1 receptors found in areas of brain that modulate nociceptive processing;
CB1 and CB2 agonists have peripheral analgesic action; cannabinoids may have anti-inflammatory effect; analgesic
effect of cannabinoids not blocked by opioid antagonists; intravenous administration of THC exerts potent
antinociceptive effects; cannabinoid-induced analgesia appears to be linked to opioid system; in rat model, cannabinoids
also effective in treating neuropathic pain; cannabinoids may provide enhanced and persistent analgesic effect
for lower doses of opioids
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| Speaker’s pilot study: objectives were to assess effects of smoked marijuana on 1) cancer pain that persisted despite
opioid treatment, 2) experimental pain model, 3) opioid-related nausea and vomiting, and 4) disposition kinetics of
background opioids; results—average reduction in daily pain 30%; experimental pain “quite diminished” and secondary
hyperalgesia decreased up to 40%; reduction in neuropathic pain 30%; outcomes-inspired follow-on study
now complete, and results being analyzed; research on cannabis hindered by numerous layers of regulations at multiple
federal government agencies and nongovernmental special-interest entities
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| Institute of Medicine (IOM): summary of efficacy of cannabinoid drugs stated that 1) accumulated data indicate potential
therapeutic value of cannabinoid drugs in relief of pain, control of nausea and vomiting, and stimulation of
appetite; 2) therapeutic benefits best established for THC; 3) effects of cannabinoids generally modest, and more
effective medications usually available; IOM also stated, “the goal of clinical trials of smoked marijuana should not
be to develop it as a licensed drug, but as a first step toward the development of nonsmoked, rapid-onset cannabinoid
delivery systems”; may take years
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| Alternative delivery system of THC: speaker investigated Volcano Vaporizer, which delivers marijuana vapor to patient
for inhalation
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| Final observations: increasing evidence that cannabinoids have antineoplastic activity; gliomas and skin tumors seem
particularly responsive, other malignancies under investigation; despite federal government’s reluctance to legalize
medicinal marijuana, public support for its legalization high; speaker thinks medicinal use of marijuana represents
“the natural evolution of medicine and where we should be going”
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Educational Objectives
| The goal of this program is to educate the listener about the therapeutic use of controlled substances. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Develop a rational approach for using opioids.
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| 2. Select patients who are appropriate candidates for receiving opioids.
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| 3. State some beneficial nonanalgesic effects of methadone.
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| 4. Discuss the difficulties involved in doing clinical research on cannabinoids.
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| 5. Summarize the medicinal benefits of cannabinoids that have been identified to date.
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Discussed on This Program
Dronabinol [Marinol]
Methadone HCl [Dolophine HCl, Methadone HCl Diskets, Methadone HCl Intensol, Methadose]
Suggested Reading
Abrams DI et al: Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled
clinical trial. Ann Intern Med 139:258, 2003; Abrams DI: Medical marijuana: tribulations and trials. J Psychoactive
Drugs 30:163, 1998; Allister SD et al: Cannabinoids selectively inhibit proliferation and induce death of cultured
human glioblastoma multiforme cells. J Neurooncol 74:31, 2005; Bredt BM, Abrams DI, et al: Short-term effects of
cannabinoids on immune phenotype and function in HIV-1-infected patients. J Clin Pharmacol 42(11 Suppl):82S,
2002; Carter GT, Abrams DI et al: Medicinal cannabis: rational guidelines for dosing. I Drugs 7(5):464, 2004; Corey
S: Recent developments in the therapeutic potential of cannabinoids. P R Health Sci J 24:19, 2005; Dalton GD et al:
Chronic Delta 9-tetrahydrocannabinol treatment produces antinociceptive tolerance in mice without altering protein
kinase A activity in mouse brain and spinal cord. Biochem Pharmacol 70:152, 2005; Fishman SM et al: Adherence
monitoring and drug surveillance in chronic opioid therapy. J Pain Symptom Manage 20:293, 2000; Fishman SM et al:
Methadone reincarnated: novel clinical applications with related concerns. Pain Med 3:339, 2002; Fishman SM et al:
The trilateral opioid contract. Bridging the pain clinic and the primary care physician through the opioid contract. J
Pain Symptom Manage 24:335, 2002; Fishman SM: Opioid side effects, addiction, and anti-inflammatory medications.
J Pain Palliat Care Pharmacother 19:51, 2005; Fox A, Bevan S: Therapeutic potential of cannabinoid receptor agonists
as analgesic agents. Expert Opin Investig Drugs 14:695, 2005; Hall W, Christie M, Currow D: Cannabinoids and cancer:
causation, remediation, and palliation. Lancet Oncol 6:35, 2005; Holden JE, Jeong Y, Forrest JM: The endogenous
opioid system and clinical pain management. AACN Clin Issues 16:291, 2005; Johnson S: Legal issues in the use
of controlled substances in pain management. Med Ethics (Burlingt, Mass) 12:4, 2005; Kraft B, Kress HG: Indirect,
CB2 receptor and mediator-dependent stimulation of human whole blood neutrophils by exogenous and endogenous
cannabinoids. J Pharmacol Exp Ther Jul 29, 2005; [Epub ahead of print]; Lawrence LL: Legal issues in pain management:
striking the balance. Emerg Med Clin North Am 23:573, 2005; Model Policy for the Use of Controlled Substances
for the Treatment of Pain. J Pain Palliat Care Pharmacother 19:73, 2005; Montane E et al: Scientific drug
information in newspapers: sensationalism and low quality. The example of therapeutic use of cannabinoids. Eur J
Clin Pharmacol 61:475, 2005; Peart JN, Gross ER, Gross GJ: Opioid-induced preconditioning: recent advances and
future perspectives. Vascul Pharmacol 42:211, 2005; Soares LG: Methadone for cancer pain: what have we learned
from clinical studies? Am J Hosp Palliat Care 22:223, 2005; Wasserman S: Medical marijuana. NCSL Legisbrief 13:1,
2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Fishman disclosed that he is a consultant for Cophalon, Inc. and Eli Lilly and Company and is a consultant, or has
received Speakers’ Bureau honoraria, grants/research support for Elan Co., Endo Pharmaceuticals, Janssen Medical
Affairs, Merck & Co., Pfizer, Inc., and Purdue Pharma, LP.
Drs. Fishman and Abrams were recorded at Pain Management and End of Life Care: A Comprehensive Approach to Patient
Care, held June 9-10, 2005, in San Francisco and sponsored by the University of California, San Francisco, Schools
of Medicine, Nursing, and Pharmacy. The Audio-Digest Foundation thanks the speakers and UCSF for their cooperation
in the production of this program.
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