Opioid Pharmacology and Considerations in Pain Management

Release Date:  May 2007

Expiration Date: May 31, 2009


Anne Zichterman, PharmD, BCPS
Assistant Professor, Department of Pharmacy
University of Tennessee College of Pharmacy


Dr. Zichterman has nothing to disclose.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Program No.: 430-000-07-012-H01
Credits: 2.0 hours (.20 ceu)

Published: May 2007
Expires: May 31, 2009

Exam processing inquiries and booklet orders to:
CE Customer Service Manager (800) 825-4696

Direct educational content inquiries to:
CE Director (800) 331-9396


This accredited program is targeted to pharmacists and pharmacist technicians.


Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients� conditions and possible contraindications or dangers in use, review of any applicable manufacturer�s product information, and comparison with recommendations of other authorities.


To educate pharmacists about the variations in opioid pharmacology and effective clinical strategies for pain management.


After completing this article, the pharmacist will be able to:

  1. Compare and contrast the differences between opioids and their pharmacologic profiles that may lead to variations in patient response.
  2. Assess the advantages and disadvantages of available routes of administration.
  3. Implement effective pain management using as-needed and scheduled regimens, dosage titration, and opioid conversion.
  4. Develop management strategies for adverse effects, and distinguish the difference between tolerance, physical dependence, and addiction.

Throughout the past century, the availability of opioids has expanded to include semisynthetic opiate derivatives (e.g., hydromorphone, hydrocodone, oxycodone, and oxymorphone) and synthetic opioid analogs (e.g., tramadol, fentanyl, meperidine, methadone, propoxyphene, and levorphanol). These drugs bind to three types of opioid receptors: mu, delta, and kappa.1 When selecting an opioid analgesic, consideration should be given to potency and efficacy, speed of onset, duration of effect, route of administration, and adverse effect profile. The opioids all have subtle differences in these aspects, and knowledge in this area may aid the practitioner in tailoring therapy for effective and safe pain management.

Opioids for Mild-to-Moderate Pain

Codeine: Codeine, like morphine, is a naturally occurring opiate. It is a weak analgesic and should be used only for mild-to-moderate pain. Use of codeine for severe pain is extremely limited due to its lack of potency; a 60-mg dose produces less analgesia than two 325-mg aspirin tablets.2

Some researchers have proposed that codeine is a pro-drug with analgesic activity dependent on its conversion to morphine by the cytochrome P-450 2D6 (CYP2D6) enzyme.2-4 If a patient is taking a drug that inhibits the CYP2D6 enzyme (e.g., a phenothiazine, haloperidol, fluoxetine, or paroxetine),4 codeine�s efficacy may be reduced. Additionally, up to 10% of the population lack the CYP2D6 enzyme and may not achieve analgesia with codeine-containing products.3

Codeine is not recommended for patients with impaired renal function; serious adverse effects have been reported when codeine is used in this setting.4,5

Hydrocodone: Hydrocodone is only available in combination with non-opioids. Compared with codeine, it provides significantly more pain relief and a longer duration of action.4,6 Hydrocodone is a prodrug metabolized by CYP2D6, with analgesic effects dependent on its active metabolite hydromorphone. Consequently, drug interactions with CYP2D6 inhibitors and genetic enzyme deficiencies may affect the analgesic benefit.3

Dose titrations are limited by the non-opioid content, which makes using this agent for severe or escalating pain difficult.6 Most hydrocodone combination products contain at least 500 mg of acetaminophen; at these dosages, the maximum 4-g dose of acetaminophen is reached after ingestion of eight tablets. If taken as commonly prescribed (one or two tablets every four to six hours), patients may exceed the maximum daily dose of acetaminophen. According to one study, 42% of acute liver failure cases in the United States resulted from acetaminophen-induced injury. Of those who unintentionally overdosed, 63% used opioid-containing compounds, most commonly hydrocodone.7 Practitioners should counsel patients to limit use of products containing acetaminophen and check ingredients of OTC pain relievers and cold remedies.

Propoxyphene: Propoxyphene is usually used alone (Darvon) or in combination with acetaminophen (Darvocet). It is structurally different from codeine and hydrocodone and more closely resembles the phenylheptylamine opioid methadone.2 It is a weak analgesic and offers no advantage over using acetaminophen alone. However, propoxyphene may cause adverse effects, such as dizziness and euphoria.8

Propoxyphene is metabolized to norpropoxyphene, which may cause irreversible cardiac toxicity and arrhythmias.2 Norpropoxyphene has a half-life of 30 to 34 hours and accumulates with repeated dosing.4 Thus, propoxyphene is not recommended for the treatment of chronic pain, elderly patients, or patients with renal insufficiency.6,9

Tramadol: Tramadol is a weak opioid analgesic that may be useful for chronic pain. It comes in three formulations and is available alone (Ultram), in combination with acetaminophen (Ultracet), and as an extended-release tablet (Ultram ER) for once-daily administration. Its unique dual mechanism includes weak binding to mu receptors and inhibition of norepinephrine and serotonin reuptake.4 The non-opioid mechanism may increase the usefulness of tramadol for neuropathic pain.10 Due to a high incidence of nausea and vomiting, dosages must be increased slowly over several weeks, thereby limiting its effectiveness for acute pain.6,10

Since seizures have been described with tramadol administration, concurrent use of monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants should be avoided.11 To lower the risk of adverse effects, the maximum dosage is 400 mg/day; however, seizures have been reported within the recommended dosing range.4 Dosages should be reduced for patients older than 75 years or for patients with renal or hepatic dysfunction.11

Tramadol is not a controlled substance and is less likely to produce significant tolerance, physical dependence, or abuse.4 However, practitioners should be cautious when prescribing this drug for patients recovering from substance abuse disorders.6

Opioids for Moderate-to-Severe Pain

Morphine: Morphine is the prototype pure mu-receptor agonist. It is extensively used and is available in a wide variety of formulations, including both immediate- and sustained-release products.

Morphine has two biologically active metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M3G does not bind to opioid receptors but acts as a neuroexcitatory agent, contributing to adverse effects such as hyperalgesia, myoclonus, and confusion. M6G exhibits opioid activity; it is at least two to four times more potent than morphine and may significantly contribute to analgesia with chronic use.1,2,12 Both metabolites are renally eliminated; accumulation of M6G may lead to oversedation and respiratory depression in patients with advanced renal impairment.1,5,12

Morphine is known to induce histamine release, which may lead to hypotension and pruritus.2 As a hydrophilic opioid, morphine has a slower onset and longer duration compared with more lipophilic opioids (e.g., fentanyl, meperidine). Like most opioids, significant first-pass metabolism reduces the amount of orally administered drug that reaches the circulation, giving a parenteral-to-oral dose ratio of 1:3.6

Hydromorphone: Hydromorphone is five to seven times more potent than morphine but is not more likely to cause adverse effects, which is a common misconception.6 Hydromorphone has an improved side effect profile over morphine, with less histamine release and no opioid-active metabolite. Consequently, hydromorphone may be a preferable option to morphine for patients with renal impairment or hemodynamic instability.5,10

The use of hydromorphone for chronic pain has been limited by the lack of a sustained-release product. The once daily�dosed Palladone was suspended and recalled by the FDA due to an interaction with alcohol that caused destruction of the timed-release mechanism.13 Hydro-morphone is currently available in parenteral, oral, and rectal immediate-release formulations. The intravenous and oral formulations are not dose equivalent, as hydromorphone also undergoes first-pass metabolism; the parenteral-to-oral dose ratio is 1:5.6

Oxycodone: Oxycodone is more potent and causes fewer severe adverse effects (e.g., histamine release, pruritus, nausea) than morphine.4,10 Oxycodone is metabolized by CYP2D6 to an active metabolite, oxymorphone, which is now available in an oral formulation. However, unlike codeine and hydrocodone, oxycodone is itself a potent analgesic. It is unknown whether oxymorphone significantly contributes to the analgesic activity of oxycodone. Patients with CYP2D6 deficiencies who do not respond well to codeine or hydrocodone may achieve more pain relief from using oxycodone.3

Oxycodone is available in combination with non-opioids or alone in immediate- and sustained-release products. For the elderly, or for patients with renal impairment, oxycodone requires less dosage adjustment and may be a safer alternative to morphine.5

Oxymorphone: Oxymorphone is approximately twice as potent as oxycodone. It is more lipophilic than morphine, allowing for a faster onset of action. It is available as an injection and as oral formulations: immediate-release (Opana) and sustained-release (Opana ER). Because it has a longer half-life than morphine, hydromorphone, and oxycodone, the immediate-release product may be dosed at longer intervals (up to every six hours).14

Fentanyl: Fentanyl is 100 times more potent than morphine when administered intravenously and is dosed in micrograms. Unlike morphine, fentanyl acts selectively at the mu receptor, leading to an improved side effect profile with negligible histamine release, less sedation, and less constipation. It is extremely lipophilic, with an almost immediate onset when administered intravenously. In addition, its duration is relatively short compared to other opioids, usually lasting only 30 to 60 minutes. Analgesic effects may be prolonged after continuous infusion or repeated administration due to the redistribution of the drug into fat stores; in these cases, the elimination half-life may be extended to 13 to 24 hours.4,6 Thus, patients undergoing weight loss who take fentanyl chronically may require a dosage reduction.15 Fentanyl has no pharmacologically active metabolites and is one of the safest options for patients with renal failure.5

Because of its quick onset and short duration, fentanyl is often used for procedural analgesia. Although these qualities make it less useful for intermittent as-needed (prn) dosing, fentanyl is gaining popularity when used via patient-controlled administration (PCA) devices for acute postoperative pain. A comparative study of opioids administered via intravenous PCA showed that fentanyl had a significantly lower rate of adverse reactions than morphine and hydromorphone.16 A fentanyl iontophoretic transdermal system for administration via PCA has been approved by the FDA and will be available to the public sometime this year. Fentanyl is also available in several other formulations, including a transdermal patch, an oral transmucosal lozenge, and the recently approved Fentora buccal tablet.

Meperidine: Despite its continued use, meperidine is not recommended as a first-line opioid analgesic.6,9,10,17,18 Meperidine is lipophilic and has a rapid onset and shorter duration of analgesia (usually 2-3 hours) than other short-acting opioids.6,17,19,20 This feature is often overlooked with a commonly prescribed four- to six-hour dosing interval, resulting in uncontrolled pain before the next dose is due. Meperidine causes euphoric effects, which may be related to its lipophilicity and rapid transport into the central nervous system (CNS).19 It has also been shown to cause more delirium than other opioid drugs.6

The clinical utility of meperidine is limited by its active metabolite, normeperidine. This metabolite is neurotoxic and can cause irritability, delirium, agitation, tremors, and seizures. Normeperidine toxicity is not reversed by administration of the opioid antagonist naloxone, which may actually worsen the effects by counteracting the depressant effect of meperidine.4,19 Accumulation of normeperidine often occurs after repeated dosing due to its extended half-life, which is five to 10 times longer than the parent drug. Because it is eliminated renally, the risk of accumulation and serious adverse effects is higher in patients with renal insufficiency.2,6,19,21

Two of the most commonly used routes of administration�oral and intramuscular�are problematic. Significant first-pass metabolism results in blood levels of normeperidine that are considerably higher when the drug is given orally. However, oral bioavailability is low, and higher dosages are required when using this route.4 The American Pain Society (APS) recommends avoiding oral meperidine use.10 Intramuscular dosing should also be avoided, since absorption of meperidine is erratic and can vary by 50% or more (even when administered at the same injection site).2,4

Meperidine inhibits the reuptake of norepinephrine and serotonin, and is contraindicated for coadministration with MAOIs. The risk of serotonin syndrome is increased with concurrent use of serotonin-receptor agonists and SSRIs.10,19

Meperidine is not recommended for PCA administration due to the high doses needed for acceptable analgesia, which can result in an increased risk of adverse effects.21 Although intermittent intravenous dosing of meperidine may be required in patients who are allergic to phenanthrene opioids such as morphine or hydromor-phone,20 its use for PCA may be obsolete given the availability of the structurally similar opioid fentanyl.

Meperidine is often used for pain associated with pancreatitis, because it is thought to cause less spasm at the sphincter of Oddi compared to other opioids. Pancreatitis treatment guidelines have listed meperidine as the opioid of choice, even as recently as the year 2000.22,23 However, early studies that supported the use of meperidine used animals or small sample sizes and did not use comparative dosages of selected opioids.20 In contrast, more recent studies indicate that at equianalgesic dosages, all opioids cause an increase in bile pressure and that there is insufficient evidence for any benefit with meperidine use.6,19-21,23 The most recent practice guideline for acute pancreatitis from the American College of Gastroenterology does not recommend the use of any particular opioid.24 Due to the risk of toxicity, meperidine should no longer be recommended for pancreatic pain.

Because of its unique toxicity profile, meperidine is not an appropriate choice for chronic pain, elderly patients, or patients with renal impairment or seizure disorders. The maximum recommended daily dosage is 600 mg per day, for less than 48 hours.10,19 Use of meperidine may be appropriate for patients who have allergic reactions to other opioids such as morphine or hydromorphone; for the treatment or prevention of drug- or blood product�induced rigors; or for treatment of postanesthesia shivering.20

Methadone: Methadone�s pharmacology is unique; unlike other opioids, methadone is a racemic mixture of both levorotary (l)- and dextrorotary (d)-isomers. The l-isomer gives methadone its opioid activity, while the disomer is an N-methyl-D-aspartate (NMDA) receptor antagonist and a norepinephrine and serotonin reuptake inhibitor.25 As the NMDA receptor has been demonstrated to play a role in the development of opioid tolerance, it is likely that the d-isomer of methadone is at least partially responsible for its increased potency in patients already receiving other opioids.1,6 Changing to methadone may benefit patients who require high doses of opioids but also experience adverse effects. Due to its complex mechanism, methadone may also have increased efficacy for neuropathic pain.25,26

Methadone�s unique mechanism and low cost have contributed to a renewed interest in its use. However, methadone�s pharmacokinetics may predispose patients to developing serious adverse effects. Methadone has the longest and most variable half-life of any of the opioids, ranging from 12 to 190 hours (the usual half-life is approximately 24 hours). The duration of analgesia is much shorter than the half-life, requiring dosing for pain every four to eight hours at the beginning of treatment and every six to 12 hours at steady state.1,6,26,27 As a result, patients may develop delayed life-threatening sedation and respiratory depression within three to five days after starting methadone therapy or increasing the dosage.6,27 Methadone is highly lipophilic and redistributes to fat stores; significant weight loss may necessitate dosage reduction.15

Methadone is metabolized by CYP3A4, with minor activity at CYP2D6. High doses may cause QTc interval prolongation and torsades de pointes. This effect may be worsened by drug interactions with CYP3A4 inhibitors or other QTc interval�prolonging agents.25,28 Some practitioners recommend avoiding use of high dosages or the 40-mg dispersible tablets for pain, which are only indicated for detoxification and maintenance of opioid addiction.29 Caution should be used whenever initiating or adjusting a methadone regimen, especially in patients who have a prior history of heart disease or are taking additional medications that may prolong the QTc interval.

Methadone�s low cost and long half-life may provide an advantage for patients who cannot tolerate or afford sustained-release opioids. Typical dosing regimens for pain are scheduled every six to eight hours, as opposed to the once-daily regimens used to prevent withdrawal in patients with opioid dependence.25 Methadone may be highly effective when used by practitioners who are familiar with its dosing and adverse effects. However, indiscriminate use may be hazardous if its safety profile is not appreciated and toxicity carefully managed. The Drug Abuse Warning Network report in 2003 indicated that in five of six states, methadone outnumbered oxycodone or hydrocodone in opiate-related deaths.30 The U.S. Department of Health and Human Services has attributed the rise in deaths to increased use of methadone as an analgesic.31 To ensure safety, patients should be closely followed by a knowledgeable physician and receive thorough instruction on how to take methadone.

Levorphanol: Levorphanol is considered a second-line opioid for patients with moderate-to-severe chronic pain who cannot tolerate other sustained-release opioids. Like methadone, levorphanol has a long half-life (usually 12-15 hours), and accumulation may result in delayed sedation and respiratory depression. Duration of analgesia is usually four to six hours, with typical dosages scheduled at six-hour intervals.4,6 Levorphanol also exhibits NMDA receptor antagonism and may provide benefit for the treatment of neuropathic pain.32 Levorphanol is available for parenteral and oral administration. The oral formulation is available only as a 2-mg tablet, which makes titration difficult.

Agonist-Antagonist Derivatives: Pentazocine, nalbuphine, and butorphanol are kappa receptor agonists and mu receptor antagonists. Conversely, buprenorphine exhibits partial activity at the mu receptor and antagonism at the kappa receptor; it is often referred to as a partial agonist.2 Although these agents cause less respiratory depression than pure mu-agonist opioids, the ceiling effect for analgesia limits the ability to titrate dosages for severe pain. Administration may cause opioid withdrawal in patients who are already receiving pure muagonist opioids. There is also a high incidence of psychomimetic effects such as confusion and hallucinations; these may be particularly severe with use of pentazocine, in elderly patients, or in patients with renal impairment.2,4 These agents are not recommended for the treatment of moderate-to-severe cancer pain or chronic pain.4,9,10 Oral formulations of buprenorphine (Subutex, Suboxone) have been approved only for the maintenance of opioid dependence and may be prescribed by certified physicians in office-based treatment programs.33

Route of Administration

Patients may require different routes of administration, especially if they are unable to ingest or tolerate oral opioids. Immediate- and sustained-release opioids are available in a variety of formulations and may be administered via several routes. Although beyond the scope of this article, intraspinal (including intrathecal and epidural) administration and PCA are additional methods of delivery.

Oral: Due to efficacy and convenience, oral administration is preferred. Immediate-release tablets like hydromorphone, oxycodone, and oxymorphone may be crushed for ease of administration. Liquid formulations of morphine, hydromorphone, oxycodone, and methadone are also available. Sustained-release products such as oxycodone (Oxycontin), oxymorphone (Opana ER), and morphine (MS Contin) should not be split or crushed since the timed-release mechanism will be destroyed, resulting in a potentially lethal overdose. Controlled-release morphine capsules (Kadian, Avinza) may be opened, and the beads of medication can be sprinkled on soft food for patients who have difficulty swallowing capsules.

Intravenous: The intravenous route provides the most rapid onset but also a shorter duration than oral or intramuscular administration. The time-to-peak effect depends on the lipophilicity of the opioid (ranging from five minutes for fentanyl to 15-30 minutes for morphine).

Subcutaneous: Subcutaneous administration may be an alternative if intravenous access cannot be obtained. Opioids may be given via this route either continuously or intermittently. Subcutaneous boluses have a slower onset and lower peak effect than intravenous administration, and volume must be limited. For this reason, hydromorphone may be preferred over morphine, as it is available as a more concentrated injectable solution.

Intramuscular: Intramuscular injections are painful, may exhibit wide fluctuations in absorption, and can lead to tissue injury. The APS advises against the use of intramuscular administration of analgesics.

Rectal: Several immediate-release opioids may be administered via this route, including morphine, hydromor-phone, and oxymorphone. Rectal absorption of opioids is variable and highly dependent on suppository placement; if inserted past the rectal sphincter, first-pass hepatic metabolism may be avoided.10 Sustained-release morphine tablets may be administered rectally every 12 hours using the same dosage as the oral route; however, some patients may require slight dosage reductions. This technique has often been used in the palliative care setting.10

Transdermal: Transdermal administration of fentanyl may be useful for patients with chronic pain who cannot take oral medications.9 The fentanyl patch (Duragesic) is designed to provide analgesia for 72 hours, although some patients may experience breakthrough pain and require dosing every 48 hours. This formulation is unique and carries a number of warnings not shared by other sustained-release opioids. Each patch contains a relatively large amount of medication, and starting an opioid-na�ve patient on a fentanyl patch could result in overmedication, sedation, and respiratory depression. As such, the fentanyl patch should be used only for opioid-tolerant patients (defined as a daily requirement of oral morphine 60 mg, or other opioid equivalent, every day for at least a week). Patients with acute pain or those who have not consistently taken opioids are not good candidates for treatment with the transdermal fentanyl patch.6,10,34

Transdermal fentanyl does not work immediately upon placement of the patch. There is a delay of 12 to 16 hours for the onset of analgesia,10 and 17 hours for blood levels to drop by half once the patch is removed.6 The lag time for effect and prolonged titration schedule of every six days should be considered when selecting a sustained-release opioid for a terminally ill patient whose analgesic requirements might undergo rapid increases.

Heat can increase absorption of fentanyl, resulting in a potentially lethal overdose.10,34 Fever over 104�F may speed delivery by as much as one third, necessitating an increase in monitoring for toxicity. Patients should be cautioned not to apply a heating source (such as a heating pad or blanket) directly to the patch.6

Oral Transmucosal and Buccal: The fentanyl oral transmucosal lozenges (Actiq) and fentanyl buccal tablets (Fentora) are approved only for the management of breakthrough cancer pain in patients who are tolerant to opioid therapy. Both are contraindicated for patients with acute pain or patients who are opioid na�ve. These formulations allow for an extremely fast onset of action�within five to 15 minutes. This provides an advantage over oral short-acting opioids, which take longer to work.

There is no strict dose conversion ratio from other immediate-release opioids to the fentanyl lozenges and buccal tablets. Patients should start with the lowest dosage of each (Actiq 200 mcg lozenge or Fentora 100 mcg buccal tablet). Doses of the lozenges and buccal tablets are not interchangeable; the Fentora buccal tablets have faster and higher absorption than the Actiq lozenges, and equivalent doses do not increase proportionally.35

As-Needed Versus Scheduled Dosing

The disadvantage of administering analgesics on a prn basis is that pain must be a problem before it can be addressed. Repeated prn dosing may result in high peaks and low troughs, causing alternating periods of uncontrolled breakthrough pain and toxicity as more doses are used to �catch up� with the pain. If pain is present for most of the day, then sustained-release or long-acting opioids administered on a scheduled basis may be preferable to maintain consistent plasma levels.10

Sustained-release and long-acting products may limit episodes of breakthrough pain, improve compliance, and help patients sleep through the night. Several products are available (TABLE 1). If cost is a concern, or if other methods are not successful, methadone or levorphanol may be options, since their long duration of action is independent of dosage formulation. The dose of the sustained-release opioid may be determined from the previous 24-hour opioid requirement. The APS recommends treating patients for 48 hours with an immediate-release opioid and then converting two thirds of the estimated daily requirement to the sustained-release regimen.10

When sustained-release opioids are used, an immediate-release opioid should be provided for prn rescue of breakthrough pain. The prn dose should equal 10% to 15% of the total daily requirement.10 If four to six rescue doses are required in a 24-hour period, the sustained-release dosage may be increased.6 A sustained-release opioid should never be used as a prn medication, since the delivery mechanism is insufficient to treat pain immediately.10


There is no ceiling effect for pure opioids. Dosage requirements vary widely among patients, and opioids should be titrated to an acceptable level of analgesia or until side effects occur. Dosage increases of 10% to 20% during the first few days, or 30% to 50% after five days of therapy, are appropriate. Elderly patients or those with comorbidities, such as pulmonary or CNS diseases, may require lower starting dosages. In addition, longer duration of analgesia has been reported for older patients, who commonly experience prolonged elimination of opioids.10

The duration of action and time to steady state must be considered when titrating an opioid dosage. The onset of oral immediate-release opioids is typically within 45 minutes, with maximum effect occurring at one to two hours. If a patient has not achieved an acceptable level of analgesia by this time, a second dose of an immediate-release opioid may be administered.10 Because transdermal fentanyl may take 48 hours to reach steady state, the first dosage adjustment may be made after three days, with subsequent increases every six days.10,34

Table 1
Sustained-Release and Long-Acting Opioids
Drug   Dosing Interval
Morphine MS Contin 8-12 hrs
  Oramorph-SR 8-12 hrs
  Kadian 12-24 hrs
  Avinza* 24 hrs
Oxycodone OxyContin 8-12 hrs
Oxymorphone Opana ER 12 hrs
Fentanyl Duragesic 48-72 hrs
Methadone   6-8 hrs
Levorphanol   6 hrs

* The maximum dosage of Avinza is 1,600 mg/day due to fumaric acid content, which may cause renal toxicity.

Dosage Conversion
When switching to another opioid, the dosage may be determined by using an equianalgesic chart (TABLE 2). Cross-tolerance among the opioids is incomplete, and calculated dose equivalents should be reduced by 30% to 50% (see PATIENT CASE for an example conversion).6,10 This empiric dose reduction is not necessary when changing between routes with the same opioid. Equianalgesic dose ratios are approximate, and individual variation may occur. Clinicians should remain attentive to the patient during the first few days after changing to a new opioid to assess for acceptable analgesia or adverse effects.10

Conversion to methadone does not involve the use of a single equianalgesic dose ratio. Methadone increases in relative potency as higher doses of other opioids are used. Due to this effect, some practitioners recommend an empiric 75% to 90% decrease in the calculated equianalgesic dose of methadone. An alternative method that determines methadone dosing ratios based on the daily requirement of oral morphine may be used (TABLE 3).35

Several dose equivalency ratios have been described for converting oral opioids to transdermal fentanyl. The APS equates each transdermal fentanyl 25 mcg per hour increment to 45 mg per day of oral morphine.10

Table 2
Equianalgesic Chart
Dose (mg)
Codeine 200 130
Hydrocodone 30
Morphine 30 10
Hydromorphone 7.5 1.5
Oxycodone 20
Oxymorphone 10 1
Fentanyl 0.1
Meperidine 300 75
Methadone 10 5
Levorphanol 4 (acute) 2 (acute)
  1 (chronic) 1 (chronic)

Note: For repeated dosing, IV and IM dose ratios are assumed to be equivalent. For single dosing, the IV dose may be lowered to half the IM dose to achieve the same peak effect.

Source: References 6, 10.


Table 3
Conversion Ratio of Oral Morphine to Oral Methadone
Daily oral
morphine dose (mg)
Conversion ratio, oral morphine to oral methadone (mg)
<100 3:1
101-300 5:1
301-600 10:1
601-800 12:1
801-1000 15:1
>1001 20:1

Note: Reduce calculated dose by 30% to 50% to account for incomplete cross-tolerance. Dose ratios do not apply to conversions from methadone to another opioid.

Source: Reference 43.


Patient Case: Opioid Conversion

A patient is receiving a hydromorphone IV infusion of 1.2 mg/h, and the physician wishes to convert to a regimen of sustained-release oral oxycodone.

1. Determine the total daily dose of hydromorphone for the previous 24 h.

Hydromorphone IV 1.2 mg/h x 24 h = hydromorphone IV 28.8 mg

2. Determine the equivalent dose of oxycodone for the daily requirement.

Hydromorphone IV 28.8 mg � 1.5 (equivalency dose for hydromorphone IV) = 19.2 mg equianalgesic dose units

19.2 mg equianalgesic dose units x 20 (equivalency dose for oxycodone po) = oxycodone 384 mg

3. Reduce the oxycodone dose for incomplete cross-tolerance.

Oxycodone 384 mg x 70% (i.e., 30% reduction) = oxycodone 269 mg

The new regimen of oxycodone may be Oxycontin 120 mg twice daily (total daily dose, 240 mg), which closely approximates the calculated total daily dose of 269 mg.

Management of Adverse Effects

Opioids share a common side effect profile, including sedation, constipation, nausea, vomiting, pruritus, myoclonus, and respiratory depression. Tolerance develops to most opioid adverse effects within a few days. Patients taking opioid therapy should be routinely assessed for the occurrence of side effects.

If opioids cause unwanted side effects, clinicians can change the dosage, schedule, or route. If analgesia suffers as a result of dosage reduction, the time interval may be decreased. Alternatively, sustained-release formulations may decrease peak effects and resulting toxicity, thereby improving the side effect profile.10 Patients with liver cirrhosis may have reduced metabolism and require extended dosing intervals of opioids.36 Changing certain opioids to a nonoral route of administration may decrease the incidence of nausea and vomiting or myoclonus.37

Opioid rotation, or changing to another opioid, may reduce side effects and/or improve efficacy if a patient is unable to tolerate a medication. Although most opioids share adverse effects at equianalgesic dosages, some opioids have slight advantages over others with decreased incidence in side effects such as constipation and histamine release. Occasionally, patients may tolerate certain opioids better than others, possibly due to genetic differences in opioid receptor subtypes.10,37,38 Opioid rotation may also decrease adverse effects caused by accumulation of toxic metabolites.2 Patients with renal insufficiency should be changed to an opioid that lacks active metabolites (TABLE 4). Acetaminophen-containing products should be avoided for patients with liver dysfunction.36

Table 4
Opioid Selection in Renal Failure
Not Recommended for Use Use with Caution Safest in Renal Insufficiency
Meperidine Hydromorphone Fentanyl
Codeine Oxycodone Methadone
Morphine Oxymorphone  

Source: References 5, 14.

Multimodal therapy with the addition of nonpharmacologic treatments (e.g., heat, cold, relaxation techniques, cognitive behavioral therapy) or non-opioid analgesics (e.g., nonsteroidal anti-inflammatory drugs or other adjuvant drugs) may improve pain control and allow for a reduction in opioid dosage. Combination pharmacotherapy relies on multiple mechanisms of action and is often more effective than using either agent alone.10

If the previous methods fail, adjuvant medications may be used for symptomatic treatment of adverse effects.

Sedation: Sedation and cognitive impairment are more likely to occur when opioid therapy is initiated or dosages are increased. If sedation persists despite opioid rotation and dosage reductions, therapy with psychostimulants may be considered. Caffeine, dextroamphetamine, methylphenidate, and modafinil have all been used for this purpose.10

Constipation: Tolerance does not develop to this adverse effect. Patients on chronic opioid therapy should receive preventive therapy with a stimulant laxative (e.g., senna or bisacodyl) to increase bowel motility. Stool softeners such as docusate may be added but are inadequate when used as monotherapy. Other classes of laxatives can be expensive and may not be effective.6,10 Bulk-forming laxatives such as Metamucil should be avoided, since concurrent therapy with opioids may result in impaction.6 Constipation may be avoided by using transdermal fentanyl, which appears to be associated with a lower incidence of this adverse effect than oral sustained-release opioids such as morphine and oxycodone.37

Nausea/Vomiting: Nausea and vomiting may be avoided by using a nonoral route of administration for the first few days until the patient develops tolerance to this side effect. However, nausea and vomiting may occasionally persist. Chronic nausea is observed in 15% to 30% of patients receiving morphine for chronic cancer pain. If changing the opioid or route of administration is not helpful, antiemetics may be used. There are no definitive studies to indicate the superiority of one antiemetic over another. Recommended agents include metoclopramide, haloperidol, prochlorperazine, phenothiazines, transdermal scopolamine, ondansetron (or another 5-HT3 antagonist), and dexamethasone.37

Pruritus: Morphine and codeine have a high incidence of histamine release and pruritus. Changing to fentanyl or oxymorphone, which both cause negligible histamine release, may avert this problem.10 Antihistamines are commonly recommended to treat itching, but there is also anecdotal evidence for success with paroxetine.37

Myoclonus: Myoclonus is uncontrolled twitching or jerking, usually of the arms or legs, that may be caused by neuroexcitatory metabolites. This adverse effect may occur with high-dose opioid therapy.6,37 Oral morphine causes a threefold higher incidence of myoclonus than intravenous morphine, implicating the role of higher M3G concentrations resulting from first-pass metabolism. Opioid rotation may eliminate this adverse effect. If myoclonus persists, adjuvants such as baclofen, diazepam, clonazepam, midazolam, valproic acid, and dantrolene sodium may be used.37

Respiratory Depression: Opioids exert a depressant effect on the respiratory center, which can slow breathing and lead to cyanosis and respiratory arrest. Pain is a powerful stimulus to counter this effect.5 Respiratory depression is rare in patients receiving chronic opioid therapy.

It can usually be avoided by careful titration but may occur in opioid na�ve patients who require high dosages for analgesia. According to the APS, �No patient has succumbed to respiratory depression while awake.� If a patient becomes overly sedated, the opioid dosage should be reduced. In emergent situations, the opioid antagonist naloxone may reverse the effect. The duration of naloxone is much shorter than that of most opioids (30-90 minutes), and repeated doses are often needed. Patients should be monitored closely for at least three hours past the time of expected peak analgesic blood concentrations.11 Prolonged naloxone opioid antagonism has been reported in patients with renal failure who received morphine, and extra care should be given to monitoring when metabolite accumulation is suspected.39

Opioid Allergy

True opioid allergies are rare.6,40 Patients frequently confuse common side effects, such as nausea or pruritus, with drug allergies. Asking the patient to describe their reaction may help to clarify whether the reported allergy involves anaphylaxis or a side effect.10

There are three classes of opioids: phenanthrenes, phenylpiperidines, and phenylheptylamines (TABLE 5).4 A patient who experiences an adverse reaction to a natural phenanthrene like codeine or morphine may not exhibit the same reaction to a semisynthetic phenanthrene; hydromorphone or oxycodone could be tried in this case. However, if the reaction is severe or if the patient describes an anaphylactic reaction such as difficulty breathing, switching to an opioid from another chemical class (such as fentanyl or methadone) may be indicated. Caution should be used, since the incidence of cross-allergy in these instances is unknown.40

Table 5
Chemical Classes of Opioids
Phenanthrenes Phenylpiperidines Phenylheptylamines
Natural Fentanyl Methadone
Codeine Meperidine Propoxyphene

Source: References 2, 40.

Tolerance, Physical Dependence, and Addiction

Tolerance occurs when a constant opioid dosage produces a decreasing effect. With the exception of constipation, tolerance develops to opioid-induced side effects (e.g., respiratory depression, sedation, nausea). Tolerance to analgesic effects may occur within the first week or two of therapy and is usually characterized by a decrease in the duration of analgesia. After this time, however, tolerance to analgesia is relatively uncommon. If a patient has been stabilized on an opioid regimen and a dosage escalation is required, the development of new pathology is the most common cause. Cross-tolerance among opioids is not complete, for either analgesic effects or toxicity.6,10

Physical dependence is a predictable pharmacologic effect that is manifested by the development of a withdrawal syndrome after abrupt discontinuation of therapy. It is often confused with addiction; however, physical dependence is unrelated to addiction and occurs with many classes of drugs, including steroids and antihypertensive agents. Physical dependence may be anticipated in patients who have taken repeated doses of an opioid for more than two weeks. A withdrawal syndrome may be avoided by tapering doses by 10% to 20% per day.6,10

Addiction is a psychological dependence, rather than dependence related to a property of the drug. The APS defines addiction as �a pattern of compulsive drug use characterized by a continued craving for an opioid and the need to use the opioid for effects other than pain relief.� Other definitions characterize addiction as �continued use despite harm.� Patients with addiction disorders make obtaining the medication the primary focus of their life and exhibit aberrant drug-seeking behaviors.10

The incidence of addiction in patients treated with opioids is widely debated and often overestimated. A frequently reported incidence of addiction of 0.01% is not likely representative of the true incidence in the population, as it was based on a retrospective chart review that excluded patients with a prior history of substance abuse from the final analysis.41 Subsequent studies have corroborated that the risk of addiction in patients with no history of substance abuse (either drugs or alcohol) is low, and most experts agree that fear of opioid addiction should not be a primary concern when initiating appropriate opioid therapy.42 Patients who have active or prior history of substance abuse disorders are at higher risk of developing opioid addiction, and may require care by specialists. The prevalence of addiction among patients treated with opioids in chronic pain centers has been reported to be between 3.2% and 18.9%.10

Pseudoaddiction is a term used to describe aberrant behavior by patients who are not truly addicted to opioids. Patients who are pseudoaddicted may use deception or illicit methods to obtain medication due to the fear of uncontrolled pain. Demanding behavior, clockwatching, and hoarding opioid analgesics are not always predictive of addiction and may instead result from a desire for pain relief. Pseudoaddiction may be distinguished from addiction in that once patients are effectively treated, aberrant or drug-seeking behaviors cease.6,10


Opioids have been considered the mainstay of cancer pain management,37 and they are increasingly used for treatment of chronic and acute noncancer pain. As understanding of the pharmacology of this class of drugs becomes more sophisticated, clinicians may anticipate dosage-limiting adverse effects and variations in individual response. Pharmacists can use this knowledge as part of a multi-disciplinary team to help guide the selection of opioids, identify correct dosages and schedules, and monitor for adverse effects. Counseling patients will aid in ensuring adherence and overall treatment success.


  1. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18(4 suppl): S3-S13.
  2. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LM, eds. Goodman & Gilman�s the Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:521-555.
  3. Armstrong SC, Cozza KL. Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality. Part II. Psychosomatics. 2003;44:515-520.
  4. Miyoshi HR, Leckband SG. Systemic opioid analgesics. In: Loeser JD, Butler SH, Chapman CR, et al, eds. Bonica�s Management of Pain. 3rd ed. Baltimore, Md: Lippincott Williams & Wilkins; 2001:1682-1709.
  5. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28:497-504.
  6. Pasero C, Portenoy RK, McCaffery M. Opioid analgesics. In: McCaffery M, Pasero C. Pain: A Clinical Manual. New York, NY: Mosby; 1999:161-199.
  7. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364-1372.
  8. Po ALW, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ. 1997;315:1565-1571.
  9. Levy MH. Pharmacologic treatment of cancer pain. N Engl J Med. 1996;335:1124-1132.
  10. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, Ill: American Pain Society; 2003.
  11. Ultram [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc.; May 2004.
  12. Wittwer E, Kern SE. Role of morphine�s metabolites in analgesia: concepts and controversies. AAPS J. 2006;8:E348-E352.
  13. FDA asks Purdue Pharma to withdraw Palladone for safety reasons [press release]. U.S. Food and Drug Administration. July 13, 2005. Available at: www.fda.gov/bbs/topics/news/2005/new01205.html. Accessed February 21, 2007.
  14. Prommer E. Oxymorphone: a review. Support Care Cancer. 2006;14:109-115.
  15. McPherson ML. Exploring the pharmacist�s role in the management of chronic pain: focus on opioid analgesics. Drug Topics. July 2005;suppl:1-10.
  16. Hutchison RW, Chon EH, et al. A comparison of fentanyl, morphine, and hydromor-phone patient-controlled intravenous delivery for acute postoperative analgesia: a multicenter study of opioid-induced adverse reactions. Hosp Pharm. 2006;41:659-663.
  17. Clinical Practice Guideline: Acute Pain Management: Operations or Medical Procedures and Trauma. Rockville, Md: U.S. Department of Health and Human Services, Agency for Health Care Policy and Research; 1992. AHCPR Publication 92-0032.
  18. Clinical Practice Guideline Number 9: Management of Cancer Pain. Rockville, Md: U.S. Department of Health and Human Services, Agency for Health Care Policy and Research; 1994. AHCPR Publication 94-0592.
  19. Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther. 2002;9:53-68.
  20. Gordon DB, Jones HD, Goshman LM, et al. A quality improvement approach to reducing use of meperidine. Jt Comm J Qual Improv. 2000;26:686-699.
  21. Seifert CF, Kennedy S. Meperidine is alive and well in the new millennium: evaluation of meperidine usage patterns and frequency of adverse drug reactions. Pharmacotherapy. 2004;24:776-783.
  22. Munoz A, Katerndahl DA. Diagnosis and management of acute pancreatitis. Am Fam Physician. 2000;62:164-174.
  23. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol. 2001;96:1266-1272.
  24. Banks PA, Freeman ML; Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101:2379-2400.
  25. Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone reincarnated: novel clinical applications with related concerns. Pain Med. 2002;3:339-348.
  26. Brown R, Kraus C, Fleming M, Reddy S. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J. 2004;80:654-659.
  27. Goodman F, Jones WN, Glassman P. Methadone dosing recommendations for treatment of chronic pain. Available at: www.pbm.va.gov/archive/methadonedosing.pdf. Accessed February 16, 2007.
  28. Krantz MJ, Mehler PS. QTc prolongation: methadone�s efficacy-safety paradox. Lancet. 2006;368:556-557.
  29. Hampton T. Methadone alert. JAMA. 2007;297:354.
  30. U.S. Department of Health and Human Services, Office of Applied Studies, Substance Abuse and Mental Health Services Administration (SAMHSA). Drug Abuse Warning Network. The DAWN Report. Opiate-related drug misuse deaths in six states: 2003. 2006;19.
  31. Centers for Disease Control and Prevention. Increase in poisoning deaths caused by non-illicit drugs�Utah, 1991�2003. Morb Mortal Wkly Rep. 2005;54:33-36.
  32. Prommer E. Levorphanol: the forgotten opioid. Support Care Cancer. 2007;15:259-264.
  33. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHS Publication No. (SMA) 04-3939. Rockville, Md: Substance Abuse and Mental Health Services Administration; 2004. Available at: buprenorphine.samhsa.gov/Bup%20Guidelines.pdf. Accessed February 19, 2007.
  34. Duragesic [package insert]. Titusville, NJ: Janssen Pharmaceutica Products, L.P.; 2005.
  35. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006;22:805-811.
  36. Gazelle G, Fine PG. Fast fact and concept #75: methadone for the treatment of pain. 2nd ed. End-of-Life/Palliative Education Resource Center. 2002. Available at: www.eperc.mcw.edu/fastFact/ff_75.htm. Accessed February 16, 2007.
  37. Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet. 1999;37:17-40.
  38. Cherny N, Ripamonti C, Pereira J. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19:2542-2554.
  39. Hanks GW, Reid C. Contribution to variability in response to opioids. Support Care Cancer. 2005;13:145-152.
  40. Hanes SD, Franklin M, Kuhl DA, Headley AS. Prolonged opioid antagonism with naloxone in chronic renal failure. Pharmacotherapy. 1999;19:897-901.
  41. Gilbar PJ, Ridge AM. Inappropriate labeling of patients as opioid allergic. J Oncol Pharm Practice. 2004;10:177-182.
  42. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980;302:123.
  43. Kanner RM, Foley KM. Patterns of narcotic drug use in a cancer pain clinic. Ann N Y Acad Sci. 1981;362:161-172.

Back to Top

  Take Test  |  View Questions