P&T News: August 1996, Vol. 17, No. 2

Management of Cancer Pain: A Closer Look at Sustained-Release Morphine, Sustained- Release Oxycodone, and Transdermal Fentanyl

Darcy L. Johnson, Pharm.D., and Amy J. Becker, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Robert Dreicer, M.D., Associate Professor, Division of Hematology/Oncology, Department of Internal Medicine

A patient's perspective:

"One of the worst aspects of cancer pain is that it's a constant reminder of the disease and of death. Many fear the pain will become unbearable before death, and those of us involved in support networks have seen these fears proven true.

Pain seems greater when dealing with it alone and an increasing number of us are finding comfort in support groups, where we also deal with issues of personal control, communication with doctors and nurses, effective adjunctive therapies, and other topics.

My dream is for a medication that can relieve my pain while leaving me alert and with no side effects. "

-Jeanne Stover3

This review focuses on opioid use in cancer pain management. Emphasis is placed upon appropriate opioid selection, dosing, and administration. The various opioid analgesics' pharmacologic and pharmacokinetic properties are discussed; the properties of morphine sulfate, oxycodone, and transdermal fentanyl are emphasized.

Opioid Classification
Opioid classification is based upon pharmacologic properties best comprehended by understanding the opioid's mechanism of action. The human body contains endogenous pain modulating substances (enkephalin, endorphin, and dynorphin) which are similar in molecular configuration to that of morphine. Both endorphins (endogenous morphine-like substances) and exogenous opioids (opioid analgesics) bind to opioid receptors in the human central nervous system (CNS) to provide analgesia and other effects. The classification of these opioid receptors is still being debated, but clearly occupation and activation of the receptors produce the pharmacologic effects. Most investigators now agree there is convincing evidence for three major opioid receptor classes in the CNS, designated mu, kappa, and delta. These receptors have distinct profiles when bound by agonists (Table 1).4

Table 1: Characteristics and Effects of Opioid Receptors
RECEPTORS	AGONIST EFFECT
Mu (u1, and u2)	Supraspinal and spinal analgesia, respiratory depression, sedation, constipation
Kappa (K1, K2, K3)	Primarily spinal analgesia, sedation, constipation, psychotomimetic effects
Delta (S1, S2)	Supraspinal and spinal analgesia
This table is not inclusive of all effects seen when the receptor is bound by an agonist. Modified from reference 4.

Opioid analgesics may be differentiated according to the receptors to which they bind and by the rate and affinity of that binding (Table 2).4 Pure opioid agonists (e.g., morphine, oxycodone, fentanyl) bind to and activate receptors. Antagonists (e.g., naloxone) bind to the receptors but do not cause the associated effects. Antagonists with higher affinities for the receptors may displace agonists with lower affinities, resulting in the termination of opioid effects and possibly withdrawal symptoms. Some drugs known as agonist-antagonist opioids (e.g., nalbuphine) act as agonists at one type of receptor and antagonists at another type of receptor. Agonist-antagonist opioids have an increased incidence of psychotomimetic adverse effects and may precipitate withdrawal symptoms in patients physically dependent on another opioid analgesic. Partial agonists (e.g., butorphenol) bind to part of a receptor and activate the receptor, but perhaps to a lesser extent than pure agonists. Thus, these opioids tend to have a ceiling dose for analgesia.

Table 2: Comparative Effects of Selected Opioids on Opioid Receptors
OPIOIDS	RECEPTOR TYPES Mu Kappa Delta
Pure Agonists Morphine Fentanyl Oxycodone	Strong agonist	Agonist K1 & K3	Data not available
Partial Agonists Butorphanol	Partial agonist	Agonist K1	Data not available
Antagonists Naloxone	Strong antagonist	Antagonist K1; Agonist K3	Antagonist
Agonist-Antagonists Nalbuphine	Antagonist	Agonist K1 and K3	Data not available
Modified from reference 4.

Opioid Selection
Based upon this classification scheme, pure agonists appear to be the drugs of choice for the management of cancer pain. These agents bind primarily to the mu receptors in the CNS and the bowel to produce their major effects. Interpatient variability occurs in response to the pure opioids leading to a wide range of intensity in pain relief and adverse effects. Most adverse effects appear to have an equal likelihood of occurring when patients receive opioid agonists. Table 3 provides a review of the management of selected side effects.

The pure opioid agonists have commonly been grouped into "weak" agonists and "strong" agonists by the World Health Organization. This differentiation is based more on convention than pharmacological properties.5 "Weak" opioid agonists (e.g., codeine ) are used to manage moderate cancer pain alone or in combination with acetaminophen or aspirin. The dose of the combination products may be increased until the maximum recommended dose of the nonopioid component is reached. For example in most patients with normal liver and renal function, 3.9 grams of aspirin or 4 grams of acetaminophen are considered to be daily limits. "Strong" opioid agonists, of which morphine is the prototype, are used in patients with moderate to severe pain. Agents with a short half-life (e.g., morphine, hydromorphone, oxycodone) are preferred for rapid titration to control pain, as well as for use in elderly patients or in patients with compromised renal or hepatic function.

Table 3: Management of Selected Opioid-Associated Adverse Effects
SIDE EFFECT	MANAGEMENT
Constipation	Scheduled prophylactic laxatives (e.g., psyllium or docusate combined with senna or milk of magnesia). Tolerance does not develop.
Nausea/Vomiting	Antiemetics (prochlorperazine, metoclopramide, meclizine) if indicated. More common with the start of opioid therapy and is usually short-lived (24h to 72h). If prolonged ( > 1 to 2 weeks), try another opioid.
Sedation	Usually more pronounced in the opioid-naive or elderly cancer patient. Tolerance usually develops; however, if it remains a concern, reducing the dose with increased frequency of administration may be helpful. If sedation becomes the dose limiting effect, judicious use of central nervous system stimulants (e.g., methylphenidate or dextroamphetamine) given in low doses may help.
Respiratory Depression	Commonly accompanied by sedation and confusion. Tolerance develops rapidly. Verbal or physical stimuli usually awakens patient. However, if life-threatening respiratory depression does occur, it can be reversed by SLOW infusion of LOW doses of naloxone (e.g., 40 to 80 mcg every 1 to 2 minutes). Titrate as needed to maintain adequate respirations and retain pain control without precipitating withdrawal.
Derived from references 3 and 9.

MORPHINE remains the opioid analgesic of choice for the management of cancer pain. It has the advantage of increased convenience as it is available in numerous formulations. Oral, intravenous, intramuscular, subcutaneous, epidural, intrathecal, sublingual, and rectal are all viable routes of morphine administration.

Immediate-release morphine is available as an oral solution and as tablets. The analgesic effect of these two short-acting preparations peaks in 30 to 60 minutes and lasts for approximately 4 hours. Appropriate immediate-release morphine use includes dose titration prior to initiating long-acting morphine therapy and "as needed" (PRN) dosing for breakthrough pain.

Long-acting or controlled-release morphine (e.g., MS Contin[R]) is a wax cellulose matrix which slowly releases morphine as it travels through the stomach and small intestine. Its analgesic effect peaks in 2 to 3 hours and lasts for 12 hours.6 The twelve-hour dosing schedule increases patient compliance and independence as well as allows patients to sleep throughout the night. This agent rarely needs to be given every 8 hours. Also, although not FDA-labeled for this route of administration, MS Contin[R] has been administered rectally, providing a noninvasive alternative for the patient unable to take oral morphine.47

OXYCODONE is a semi-synthetic analog of morphine. It is of similar or greater potency to morphine. Although this agent is not available as an injection, several oral formulations exist which promote its use in the management of pain ranging from mild to severe. The combination products with aspirin (e.g., Percodan[R]) and acetaminophen (e.g., Percocet[R]) allow for enhanced analgesic efficacy and treatment of concurrent symptoms that may exacerbate pain. Oxycodone is also available in single- agent oral solution and immediate-release tablets. The analgesic effect of these agents peaks in 30 to 60 minutes and lasts for approximately 4 hours. Appropriate use of these agents includes dose titration prior to initiating a long-acting regimen and PRN dosing for breakthrough pain. It is important not to exceed the recommended daily amounts of the nonopioid component when giving the combination products (e.g., aspirin 3.9 grams and acetaminophen 4 grams).

Controlled-release oxycodone tablets (Oxy Contin[R]) provide controlled delivery of oxycodone over 12 hours. Analgesic onset occurs within one hour and continues for 12 hours to provide constant control. This new formulation is an alternative for patients who have not tolerated morphine after an adequate trial. Patients receiving Oxy Contin[R] should be forewarned that they may pass empty matrix "ghosts" (tablets) in their stool and that this is of no concern as little or no oxycodone is contained within these.

FENTANYL, a synthetic opioid agonist, is available in transdermal patches (Duragesic[R]) to be administered every 72 hours (a few patients may require every 48-hour administration). Upon patch application, clinical analgesia onset occurs after 12 to 14 hours with achievement of steady state after 72 hours. Due to the slow onset of action and extended time until steady state is reached, titration of transdermal fentanyl is difficult. Therefore, it should not be the initial opioid utilized to control pain nor should it be used in patients with unstable or rapidly increasing pain. Another factor to consider with transdermal fentanyl delivery is the formation of a subcutaneous depot. This makes immediate discontinuation difficult, as fentanyl absorption continues for 16 to 24 hours after patch removal. With an opioid-naive patient, this long- lasting absorption may place the patient at greater risk by producing respiratory depression due to an initial lack of tolerance.

These properties limit appropriate transdermal fentanyl use to non-opioid-naive, chronic, stable pain patients unable to take oral agents or intolerant of other available opioids. If transdermal fentanyl is indicated in a patient, it is important to prescribe an agent for breakthrough pain. This will most likely be an opioid that can be either given rectally or parenterally in those patients unable to take oral agents.

HYDROMORPHONE is an opioid alternative for the patient with decreased renal function, as none of its metabolites has been found to be toxic. Although only the immediate-release tablets and the injection are available currently in the United States, sustained-release products of hydromorphone are now available in other countries. METHADONE is another available opioid which may be used for the management of cancer pain. However, cumulative effects do occur with repeated dosing, making this agent much more difficult to titrate without oversedating. MEPER1DINE is a poor opioid for chronic use, or in patients with renal dysfunction. Accumulation of one of its renally-excreted metabolites, normeperidine, may cause seizure activity. Although CODEINE may be used in those patients with mild pain, gastrointestinal toxicity (e.g., constipation, nausea, and vomiting) preclude using large doses of this opioid.

Dosing
For the treatment of cancer pain, opioid analgesics should be given on a regular basis with the next dose given before the previous one wears off to achieve continuous pain relief. The dose should be titrated, gradually increasing the dose until the patient is comfortable. If controlled-release opioid products are being used, "as needed" immediate-release agents should be given for breakthrough pain. When a new drug is started or a patient has increasing pain, these supplemental doses will assist in defining the best daily dosing requirements for the patient. Underdosing is not appropriate in the treatment of cancer pain. Fear of addiction should not be a concern as wide clinical experience has shown that psychological dependence rarely, if ever, occurs in a cancer patient receiving opioids for chronic pain. Pain is an important symptom that can and must be treated.

The profiles of selected opioid agonists with respect to pharmacokinetic parameters, equianalgesic doses and cost of therapy are summarized in Table 4. This table and Table 5 describing opioid equianalgesic dose conversions should assist in making conversions from one opioid to another.

Recommendations
Although individual assessment is needed, cancer pain management often involves the use of opioids. Morphine is considered to be the opioid analgesic of choice as numerous formulations are available for use in a variety of settings. This pure, "strong" opioid agonist may be given initially to patients with mild pain as immediate-release tablets, in small doses, on an "as needed" basis. As pain increases, titration to the controlled-release product (MS Contin[R]) will provide for continuous pain control. Although there is no upper oral dose limit, parenteral morphine may be indicated in those patients with very severe pain or who are unable to take oral agents. If the patient has failed morphine due to a true morphine allergy (anaphylaxis), experiences continuous nausea and vomiting, or is intolerant of this agent for another specified reason, oxycodone is a reasonable alternative. Oxycodone has many of the same benefits as morphine with the exception that no parenteral product is available and the controlled- release agent, Oxy Contin[R], is expensive. Transdermal fentanyl use should be limited to those patients unable to take oral agents, or those patients intolerant to the other opioid agonists.

Table 4: Comparison of Opioid Agonists with Respect to Equianalgesic Dose and Dosing Interval
Opioid	Route	Dose Equivalence[a,b] (mg)	Recommended Dosing Interval (hours)	Comments
Morphine	parenteral	10	3-4 or CI[d]
Immediate-release	oral, rectal	30	3-4
Sustained-release (MS Contin[R])	oral, rectal	30	12
Oxycodone
Immediate-release	oral	30	3-4	1
Sustained-release (OxyContin[R])	oral	30	12
Fentanyl	transdermal	0.5	72
Hydromorphone	parenteral oral	1.5 7.5	3-4 or CI 3-4
Methadone	parenteral oral	10 20	4-8 4-8	2
Meperidine	parenteral oral	75 300	3-4 3-4	3
Codeine	parenteral oral	130 200	3-4 3-4	4
[a] Dose equivalences are approximate. [b] When convening from one opioid to another, it is recommended that the calculated dose be reduced by 50% to account for incomplete cross-tolerance. Appropriate titration of dosage should then be performed as clinically indicated. [c] UIHC acquisition costs per day for doses equivalent to transdermal fentanyl 25 mcg/hr [d] Continuous infusion 1. Combined with aspirin or acetaminophen for moderate pain; also available without co-analgesic. 2. Should only be prescribed by physicians experienced in monitoring the cumulative effects which occur with repeated dosing. 3. Not recommended for cancer pain due to potential toxicity of metabolite, normeperidine. 4. Usually combined with acetaminophen for treatment of mild pain. Derived from references 3 and 9.

Table 5. OPIOID EQUIANALGESIC DOSE CONVERSION GUIDELINES

1. Calculate the total daily dose of all opioids used. 2. If the patient is taking more than one opioid, convert all agents to an equivalent dose of morphine using Table 4. 3. Determine equivalent dose of new opioid from Table 4. 4. Initiate new opioid at 1/2 of the calculated dose as tolerance is not complete from one opioid to another. Titrate up or down depending upon pain relief and development of side effects (such as sedation). 5. Provide for "rescue" doses. (Each rescue dose should be 5 to 15 % of the total daily maintenance dose and should be administered every 2 to 4 hours as needed for pain.) [Example] BJ is taking 2 Percocet[R] (oxycodone 5 mg and acetaminophen 325 mg in each tablet) every 4 hours (scheduled). A long-acting agent is needed to allow the patient to maintain more stable pain control as well as to sleep throughout the night. Therapy with MS Contin[R] will be initiated. The appropriate initial regimen is calculated: a. A regimen of oxycodone 10 mg every 4 hours=60 mg in 24 hours. b. This is equivalent to 60 mg of oral morphine. c. As tolerance is not complete, 30 mg of MS Contin[R] (1/2 of 60 ma) should be given daily. d. An appropriate prescription would be MS Contin[R] 15 mg every 12 hours, plus morphine immediate release 5 mg (5 to 15 % of total daily dose) every 2 to 4 hours as needed (PRN) for pain.

References

1. Anesth Analg 1993;76:402-16.

2. Foley KM. Pain syndromes in patients with cancer. In: Bonica JJ, Ventafridda V, editors. International Symposium on Pain of Advanced Cancer; 1978;Vence. Vol. 2. Advances in pain research and therapy. New York: Raven Press, LTD.; 1979: 59-75.

3. Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No.9. AHCPR Publication No. 940592. Rockville, MD. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, March 1994.

4. Resine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, et al., Goodman & Gilman's the pharmacologic basis of therapeutics . 9th edition. New York, St. Louis, San Francisco: McGraw-Hill; 1996: 521-55.

5. Oncology 1992;6(2Suppl):86-98.

6. Cancer 1989;63:2275-83.

7. Am J Hospice Care 1989;6:34-5.

8. J Clin Oncol 1995;13(6):1520-7.

9. Anesth 1996;84:1243-57.

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Pharmacy and Therapeutics Subcommittee Actions

Drugs Added to Stock

FLUCONAZOLE (DIFLUCAN[R]) SUSPENSION Fluconazole is now commercially available as a powder for oral suspension (10 mg per ml when reconstituted).

ORAL REHYDRATION SALTS, CITRATE (W.H.O. FORMULA) Each 27.9 gram packet when dissolved in one liter of drinking water provides sodium 90 mEq/L, potassium 20 mEq/L, chloride 80 mEq/L, citrate 10 mEq/L, and glucose 111 mEq/L.

PRAVASTATIN (PRAVACHOL[R]) TABLETS The 40 mg strength has been added to stock.

Drugs Deleted From Stock

POTASSIUM CHLORIDE (KLORVESS[R]) EFFERVESCENT TABLETS Discontinued by the manufacturer. Potassium chloride and potassium gluconate oral solutions are available.

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