Safe Oral Equianalgesic Opioid Dosing for Patients With Moderate-to-severe Pain
Samuel M. Galvagno, Jr, DO, Brigham and Women's Hospital, Darin J. Correll, MD, Harvard Medical School, and Sanjeet Narang, MD, Harvard Medical School
Published Online: May 17, 2007 - 11:48:22 PM (CDT)
Samuel M. Galvagno, Jr, DO Resident Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women?s Hospital
Darin J. Correll, MD Director of Postoperative Pain Service Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women?s Hospital Instructor in Anesthesia Harvard Medical School
Sanjeet Narang, MD Attending Physician Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women?s Hospital Instructor in Anesthesia Harvard Medical School
Boston, Mass
Opioids remain the cornerstone of management for patients with moderate-to-severe pain, but many physicians underprescribe them because of ignorance or misconceptions. The oral route is preferred because of safety, cost, ease of administration, and patient comfort. With careful monitoring, opioids are safe and effective analgesic choices. This article attempts to clarify misunderstandings about the use of short-acting and sustained-release opioids, as well as equianalgesic dosing. Definitions of pertinent concepts are provided, and strategies for parenteral-to-oral conversion are outlined, as well as the rationale for avoiding potentially hazardous opioids. A patient education guide for methadone use is also included.
Opioids remain the analgesic of choice for the control of moderate-to-severe pain. As pain continues to be ubiquitous in medical practice, many guidelines on analgesic treatment and quality assurance have been issued by the US Government,1 the American Pain Society,2 and the World Health Organization.3 Although opioids remain our most powerful analgesics, ignorance, prejudice, failure to routinely assess pain and pain relief, and numerous other factors related to all levels of society and the healthcare system continue to hinder optimum use of these agents.4
Misunderstandings about appropriate dosing of oral opioids may lead to needless suffering and the development of untoward emotional and cognitive responses that detract from quality of life. The purpose of this article is to enhance understanding about the selection of and equianalgesic dosing for oral opioids. A thorough discussion regarding agonist-antagonist agents, other opioid-related compounds, and opioid-tolerant patients is beyond the scope of this review.
Definitions ?Opiate? is the term used to describe analgesic agents derived from any of the 20 distinct alkaloids of the opium poppy. ?Opioid? refers to the class of analgesics that includes all exogenous substances, natural and synthetic, that bind specifically to opioid receptors.5 The term ?opioid? is preferred to ?narcotic?; the latter refers to a variety of pharmacologic classes and is associated with negative connotations that may impose psychological barriers to pain management.6 Tolerance and dependence are not synonymous with addiction. The definitions relevant to this discussion are listed in Table 1.
Pharmacology Opioids bind to stereospecific ?, δ, and κ receptors in the central nervous system (CNS). Activation of these receptors decreases neurotransmission via presynaptic inhibition of calcium channels, leading to a decreased release of acetylcholine, dopamine, norepinephrine, substance P, and other neurotransmitters.5 Opioid binding also results in a postsynaptic reduction of neural transmission by increasing potassium conductance. In addition, opioids act on other tissues outside the CNS (eg, peripheral nerves, joints, lungs) and exhibit action at the site of inflammation.5,7
It is generally recommended to use pure opioid agonists, especially for patients with moderate-to-severe pain, as opposed to agonist-antagonists. Table 2 outlines the classification of frequently used opioids.
Empiric Dosing The oral route for opioid dosing is usually preferred to the parenteral route because of its convenience, flexibility, and relatively predictable pharmacokinetics. For most opioids, peak drug effects are 1 to 2 hours after oral administration. With the exception of methadone HCl (Dolophine, Methadose), the elimination half-life of most opioids is short enough that a steady state is reached in about 1 day.6 Table 3 lists the characteristics of opioids commonly used in the United States.
The standard by which all opioid analgesics are compared is a 10-mg dose of parenteral morphine sulfate.8 Equianalgesic dose data are derived from single-dose relative potency studies that have compared parenteral and oral doses of opioids in patients with postoperative and cancer pain.8,9
In an effort to analyze comparative single-dose data from randomized, placebo-controlled trials in patients with moderate-to-severe pain, investigators at Oxford University formulated the Oxford League Table of Analgesics.9 This table provides information on the number needed to treat to achieve a 50% reduction in pain with different opioid and nonopioid analgesics.
The recommended starting doses and intervals for opioid-na?ve adults are listed in Table 4. Efficacy relates to the proportion of available receptors that an agonist needs to bind to in order to exert its full effect. There are limited data to support differences in efficacy among the opioid agonists in opioid-na?ve patients.
The selection of a specific agent often depends on whether a patient has a documented allergy, the presence of side effects, or when increasing dosages fail to control pain. Efficacy may become relevant in opioid-tolerant patients (ie, with downregulated opioid receptors) in whom low-efficacy opioids?such as codeine, hydrocodone bitartrate (eg, Lortab, Vicodin, Zydone), propoxyphene (Darvon), meperidine HCl (Demerol), and morphine?often cannot provide adequate analgesia, because not enough receptors are available. In opioid-tolerant patients, these agents act as partial agonists. Accordingly, high-efficacy opioids, such as hydromorphone HCl (Dilaudid), oxycodone HCl (eg, M-oxy, OxyContin, Roxicodone), and methadone, are more likely to result in better analgesia.10
The optimal analgesic dose varies widely among patients; hence, it is important to ask the patient which opioids have worked in the past. There are at least 10 different ?-receptor subtypes; their expression differs between individuals, and the various opioids have different levels of effect on each receptor subtype. This may explain the between-patient variations in opioid efficacy and side effects.11
Patients should be monitored closely for effectiveness and adverse events whenever the agent or route of administration is changed or another analgesic is added to the regimen.
All opioids should be used with caution in patients with renal or hepatic insufficiency. Morphine is relatively contraindicated in patients with severe renal insufficiency because of the accumulation of the metabolite, morphine-6-glucuronide, which can lead to sedation and respiratory depression. It should be noted that hydromorphone also has a metabolite (hydromorphone-3-glucuronide) that may accumulate in patients with renal failure.
By activating multiple pain-inhibitory pathways, combination analgesics act synergistically to provide more effective relief for a broader spectrum of pain, while limiting adverse effects (Table 5). Data support the practice of multimodal therapy, including the concomitant use of opioids with agents that have different mechanisms of action, such as nonsteroidal antiinflammatory drugs or acetaminophen.9,12
The number needed to treat is likely to be lower than that for a single opioid when combination preparations are used.9 In other words, when opioids are combined with other analgesics, more patients will benefit from effective analgesia.
Preparations containing acetaminophen must be used with caution. The total daily acetaminophen dose for adults should not exceed 4000 mg; higher dosages may be associated with hepatic toxicity.12 In patients with hepatic dysfunction or chronic alcohol use (ie, more than 2 drinks daily), no more than 1000 to 2000 mg of acetaminophen should be taken daily.12-14 For children who weigh less than 45 kg, the total daily dose of acetaminophen should not exceed 90 mg/kg.12
Switching from Parenteral to Oral Opioids The first step when switching from a parenteral to an oral agent is to calculate the total daily dose of the parenteral opioid and convert it to an equivalent 24-hour oral dose, using an equianalgesic chart (Table 3). Incomplete cross-tolerance exists between the various opioids, and some patients will not be as tolerant to a new opioid agonist. Thus, when converting between opioids in a patient whose pain is being controlled with one agent, the calculated equianalgesic dose of the new agent must be reduced by 25% to 75% to prevent excessive sedation and respiratory depression. The final calculated oral dose is then divided according to the dosing schedule for that particular agent. The Figure illustrates 4 simple steps for converting intravenous hydromorphone to oral oxycodone. Computerized programs are available to expedite calculations, including the personal digital assistant application designed by physicians at Johns Hopkins University15 and the readily available Epocrates.
Opioids to Avoid ? Codeine is not a good first choice, because approximately 7% to 10% of whites do not have an active form of the enzyme (ie, cytochrome P-450 2D6) necessary to convert codeine into its active metabolite, morphine.16 Such patients do not experience appreciable analgesia but are still likely to have the side effects, including dizziness, nausea, and constipation, that frequently occur with this agent. The analgesic properties of codeine are not as profound as those of other opioids, and this agent is typically reserved for use in patients with mild pain. ? Meperidine is a synthetic opioid with a short duration of action, a toxic metabolite, and relatively low potency and efficacy. Normeperidine is a neurotoxic compound that accumulates in the elderly and in patients with renal dysfunction. This metabolite can cause dysphoria, seizures, tremor, myoclonus, and nervousness.17 The half-life of normeperidine in patients with normal renal function is 15 to 30 hours.17 The American Pain Society recommends avoiding meperidine for the treatment of cancer pain whenever possible.18 ? Propoxyphene (eg, Darvon, Darvocet, Balacet) is a synthetic oral opioid that is often combined with acetaminophen for the treatment of mild-to-moderate pain. Most authorities advise limiting the use of this agent, since severe adverse effects, such as cardiotoxicity and pulmonary edema, are possible.17 These adverse effects can be attributed to the toxicity of norpropoxyphene, a metabolite that has a half-life of 30 to 36 hours. Elderly patients taking propoxyphene have been shown to be at increased risk for falls and related injuries.19 Furthermore, propoxyphene has not been found to be any more effective than acetaminophen.17 ? Hydrocodone is often regarded as having a higher potential for dependence than other opioid combinations, although scant prospective data exist to support this view. In a retrospective study of 534 patients, hydrocodone was the most frequently mentioned opioid preparation associated with problematic use (53%), followed by oxycodone (19%).20 Hydrocodone use needs to be monitored closely, because of the acetaminophen component in many of the available preparations. Moreover, since hydrocodone is a low-potency and low-efficacy drug, it should not be used to treat moderate-to-severe pain.
Long-Acting Opioids Sustained-release (SR) formulations should only be initiated in the acute setting when it is assumed that the pain generator will exist for an extended period of time. If increasing the dosage of an SR opioid, it should be increased by 50% to 100% of the total 24-hour breakthrough dose used. In other words, if a patient is taking an SR agent and requires more than 4 rescue doses of a shorter-acting agent to adequately treat the pain, the total dose of the SR agent must be increased.
When using an SR opioid, supplementary doses of an immediate-release opioid equivalent to 10% to 15% of the 24-hour total of the long-acting opioid should be used on an as-needed basis every 2 to 4 hours. When weaning a patient from long-acting agents, decrease the dose by 25% to 50% every 2 days. Once the patient has stopped taking the SR form, the immediate-release agent can be similarly weaned, provided the patient is comfortable.
Transdermal fentanyl (Duragesic) is not appropriate for acute pain, especially in the opioid-na?ve patient. It has a black box warning against its use in the acute setting because of the risk of severe respiratory depression, since plasma levels peak over a few days (24-72 hours)?at the same time that the acute pain is decreasing. The mean elimination half-life of transdermal fentanyl is 17 hours.
Morphine is available in several SR formulations (eg, Avinza, Kadian, MS Contin, Oramorph SR) that can be used for 12-hour dosing. The main difference between the formulations is that, unlike all other SR opioids that must be swallowed whole, Kadian and Avinza are supplied as a capsule that can be opened, allowing its contents to be sprinkled on food or administered via a gastric feeding tube. This type of administration will not affect its SR profile.
Controlled-release oxycodone (OxyContin) is another oral opioid available for 12-hour dosing.12 This agent is well absorbed, with an oral bioavailability of more than 60%, providing stable plasma concentrations for the treatment of moderate-to-severe pain.5 Oxycodone is metabolized in the liver to the active metabolite oxymorphone. Approximately 5% to 10% of whites and 1% to 4% of most other ethnic groups do not have the enzymes required to metabolize oxycodone; these ?poor metabolizers? may be less responsive to the analgesic effect of oxycodone.21 The exact contribution of oxymorphone to oxycodone?s analgesic effect is unknown.
Controlled-release oxycodone has been shown to be effective for cancer pain, chronic nonmalignant pain, and acute pain. An extended-release preparation of oxymorphone (Opana ER), the active metabolite of oxycodone, was recently introduced for 12-hour dosing.
The use of methadone requires an understanding of its unique pharmacology.22 The most important characteristic to be aware of when switching from another opioid to methadone is its dose-dependent potency. Methadone has excellent oral bioavailability and is metabolized extensively in the liver to inactive metabolites. However, impaired liver function does appear to significantly alter its pharmacokinetics. It is not appropriate as a first-line agent in the acute setting, especially in the opioid na?ve. Methadone is, however, a viable alternative for patients who are opioid tolerant, especially when their pain is poorly controlled with other agents. Patients who have taken methadone for an extended period of time seem to be extremely tolerant to the analgesic effects of other opioids.23 Because of methadone?s long half-life, it takes 2 to 5 days to reach stable plasma concentrations. Thus, the patient will need to be evaluated during this time to monitor for side effects, and downward dose adjustments may be needed.
Conclusion Opioids are an important class of pharmacotherapeutic agents that must be included in the armamentarium of any clinician who treats moderate-to-severe pain. By applying basic principles of pharmacology and equianalgesic dosing strategies, one can safely help attenuate the unpleasant sensory and emotional experiences associated with actual or potential tissue damage. The oral route is preferred because of convenience, flexibility, and predictable results. Physicians should use equianalgesic programs or charts when converting from parenteral to oral opioids. Although opioids are not appropriate for all patients with moderate-to-severe pain, they should not be denied to those who can clearly benefit from them.
Self-assessment test 1. All the following statements are correct, except: A. Opioid is the preferred terminology over narcotic B. Tolerance is the result of downregulation of the agonist?s receptors C. Dependence is synonymous with addiction D. Pseudoaddiction is an iatrogenic condition
2. Which one of these agents is recommended for patients with moderate-to-severe pain? A. Methadone B. Meperidine C. Propoxyphene D. Hydrocodone
3. The following initial oral doses are correct for opioid-na?ve patients, except: A. Tramadol, 25 mg every 4-6 hours B. Oxycodone, 10 mg every 3-4 hours C. Morphine, 20 mg every 3-4 hours D. Oxymorphone, 10 mg every 4-6 hours
4. What is the best strategy when increasing the dose of a sustained-release opioid? A. Increase dose by 10% to 15% of the 24-hour total dose B. Increase dose by 10% to 15% weekly C. Increase dose by 25% to 50% every 2 days D. Increase dose by 50% to 100% of the total 24-hour breakthrough dose
5. Which of the following agents has the longest duration of action? A. IV morphine B. Oxycodone C. Tramadol D. Transdermal fentanyl
2. Miaskowski C, Cleary J, Burney R, et al. Guideline for the Management of Cancer Pain in Adults and Children. Glenview, Ill: American Pain Society; 2004.
3. WHO Expert Committee. Cancer Relief and Palliative Care. Geneva, Switzerland: World Health Organization; 1990.
4. McQuay H. Opioids in pain management. Lancet. 1999;353: 2229-2232.
5. Stoelting RK, Hillier SC. Pharmacology & Physiology in Anesthetic Practice. 4th ed. New York, NY: Lippincott Williams & Wilkins; 2006: 87-117.
6. Strassels SA, McNicol E, Suleman R. Postoperative pain management: a practical review, part 1. Am J Health Syst Pharm. 2005;62: 1904-1916.
7. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med. 1995;332:1685-1690.
8. Pereira J, Lawlor P, Vigano A, et al. Equianalgesic dose ratios for opioids. A critical review and proposals for long-term dosing. J Pain Symptom Manage. 2001;22:672-687.
10. Abram SE, Mampilly GA, Milosavljevic D. Assessment of the potency and intrinsic activity of systemic versus intrathecal opioids in rats. Anesthesiology. 1997;87:127-134; discussion 27A-29A.
12. Ashburn MA, Lipman AG, eds. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, Ill: American Pain Society; 2003:1-33.
13. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272: 1845-1850.
14. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure [published correction appears in Hepatology. 1995;22:1898]. Hepatology. 1995;22:767-773.
15. Grossman SA, Nesbit S, Loscalzo M. Hopkins Opioid Program. Version 3.2.2. Available at www.hopkinsopioidprogram.org. Accessed December 15, 2006.
16. Cascorbi I. Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest. 2003;33(suppl 2):17-22.
17. Strassels SA, McNicol E, Suleman R. Postoperative pain management: a practical review, part 2. Am J Health Syst Pharm. 2005;62: 2019-2025.
18. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. Skokie, Ill: American Pain Society; 1992.
19. Kamal-Bahl SJ, Doshi JA, Stuart BC, et al. Propoxyphene use by community-dwelling and institutionalized elderly Medicare beneficiaries. J Am Geriatr Soc. 2003;51:1099-1104.
20. Miller NS, Greenfeld A. Patient characteristics and risks factors for development of dependence on hydrocodone and oxycodone. Am J Ther. 2004;11:26-32.
21. Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60:284-295.
22. Peng PW, Tumber PS, Gourlay D. Perioperative pain management of patients on methadone therapy. Can J Anaesth. 2005;52:513-523.
23. Doverty M, Somogyi AA, White JM, et al. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine. Pain. 2001;93:155-163.
Answers: 1. C; 2. A; 3. A; 4. D; 5. D.
Patient Information Precautions for Patients Taking Methadone In 2006, the FDA issued an alert to physicians who prescribe methadone following reports of death and life-threatening side effects in patients taking methadone. These serious consequences have occurred in patients who had just recently been taking methadone for pain control, as well as in patients who had switched to methadone after being treated for serious pain with other strong and addictive pain relievers.
If you are taking methadone, you must remember that methadone can cause slow or shallow breathing and dangerous changes in heart beat, and you will often not be aware of these changes.
Like other opioids, methadone is habit-forming, and using it can create an addiction to the drug itself.
The FDA stresses that methadone should only be taken by people with moderate-to-severe pain if the pain is not controlled with other nonnarcotic pain medications. Pain relief from 1 dose of methadone lasts about 4 to 8 hours, but the drug remains in your body much longer, for as long as 59 hours after it was taken.
Therefore, you may often feel the need for more pain relief before methadone exits your body, and the drug can accumulate to levels that are toxic when taken too often, or in large doses, or when combined with other medicines or supplements.
If you are taking methadone, you must check with your doctor regularly to make sure you don?t have serious side effects. Also make sure that your doctor is aware of the prescribing information for this drug and the risks associated with it.
Patients taking methadone must be aware of the following safety information:
Use methadone exactly as written on the container. Taking more methadone than prescribed can cause your breathing to slow or stop and can even cause death. If your pain is not controlled with the drug, talk to your doctor about it. Never take more than the prescribed amount without first consulting with your doctor. If you?re not sure how many pills you may take each day, ask your doctor or pharmacist.
If you?re taking methadone, do not start or stop other medicines or dietary supplements without talking to your physician. Using additional medicines or natural supplements while taking methadone can reduce the effect of methadone on your pain and provide you with less pain relief.
Mixing methadone with other medicines is very dangerous and can cause death. If you?re taking other medications or supplements while also taking methadone, your doctor should monitor you carefully to make sure you do not have too much methadone in your body; this could lead to dangerous changes in breathing or heart beat that can be life-threatening and even cause death.
Get familiar with the signs of methadone overdose. If you are experiencing any of the following problems while taking methadone, get medical attention right away:
? Trouble breathing or shallow breathing ? Extreme tiredness or sleepiness ? Blurred vision ? Inability to think clearly, or talk or walk normally ? Feeling faint, dizzy, or confused.
