Opioids: Clinical Use - Clinical Tree

SUMMARY

The pain-relieving effect of opioids was acknowledged early in the history of medicine. However, their abuse potential and adverse effects have resulted in widespread “opiophobia,” a phenomenon of customary underutilization of opioids. The major barriers to appropriate opioid use are insufficient knowledge, inappropriate attitudes, and economics.

Traditionally, opioids have been classified as strong and weak opioids, but a functional classification of opioids based on their intrinsic activity at the receptor level is clinically more useful. In addition, opioids with activity at non-opioid receptors, such as methadone, tramadol, and tapentadol, offer useful treatment options.

Various routes of opioid administration have been described, each with its advantages and disadvantages. The oral route of administration remains the first-line option; other non-invasive routes such as transdermal patches, iontophoresis, and the nasal and inhalational routes have also been used successfully. Doses and dosing intervals depend on the pharmacokinetics of the drug, mode of delivery, and individual patient factors.

The adverse effects of opioids are mediated primarily through the opioid receptor and show wide inter- and intra-individual variability. The key to minimizing side effects is to titrate the drugs to effect and anticipate the risk for adverse effects during initiation, escalation, and withdrawal of therapy. There is good evidence that opioid rotation plus substitution is useful in reducing or limiting side effects and enhancing analgesia. Tables of equianalgesic doses should be used with caution in view of the wide interindividual variability.

Parenteral opioids remain the mainstay in the management of severe acute pain, ideally titrated intravenously, if available, via patient-controlled analgesia devices. Oral opioids can often be used subsequently.

Oral opioids should be used primarily for the management of cancer pain according to World Health Organization guidelines.

Management of chronic pain of non-malignant origin with opioids is a complex issue. Although opioids have proven efficacy in relieving persistent nociceptive and neuropathic pain, they are beneficial only in a small subpopulation of chronic pain sufferers. Here, they should be seen as one component of multimodal pain management. To identify suitable patients, most international and national guidelines recommend a trial period of sustained-release opioids with clear and realistic preset goals of therapy, in particular with regard to improved function, before venturing into long-term opioid therapy with careful monitoring for aberrant drug-taking behavior.

Introduction

The pain-relieving effects of opioids were put to use as early as 4000 bc . However, their sedative effects and abuse potential also became evident quickly. Ever since, humankind has tried to find a balance between licit and illicit use, therapeutic versus adverse effects, medical needs, and legal issues. Despite all the legal, administrative, and social interference, no other drug in the history of medicine has remained in use for as long as opioids. This by itself indicates their relevance in the relief of pain, with side effects and abuse potential being accepted as an inevitable curse.

Barriers to Clinical use of Opioids

Major barriers to opioid use continue to exist in many situations and many countries, although major progress has been made, primarily because of the relentless efforts of the . The major barriers are insufficient knowledge, inappropriate attitudes, regulatory and organizational issues, and economics ( ). “Opiophobia” ( ), defined as “customary underutilisation of opioid analgesics based on irrational and undocumented fear,” is a behavior that is modeled, reinforced, and perpetuated at all levels of the health and legal system, beginning with the attitudes of government bodies, continuing with physicians, nurses, pharmacists, and allied health professionals, and finishing with the patients, their relatives, and the general population ( ).

The insufficient and inappropriate knowledge about the pharmacology of opioids is largely a result of the “dual pharmacology” of opioids, that is, the significant differences between opioid laboratory pharmacology (in experimental animals, healthy volunteers, addicts) and opioid clinical pharmacology (in pain patients) ( ). These differences are primarily explained by the absence or presence of pain and lead to inappropriate fear of opioid-related adverse effects such as respiratory depression, tolerance, physical dependence, and psychological addiction. As an example, deficits in knowledge about the difference between physical dependence and psychological addiction influence drug dispensing by pharmacists ( ).

Even with good factual knowledge, a positive intention can lead to a negative outcome driven by attitude. A study revealed an overall positive attitude of nurses toward the use of opioids, with 94% approving the use of opioids for patient comfort ( ). The same study also stated that one-third of the nurses would administer the least possible opioid prescribed and nearly half of them would encourage the patient to have a non-opioid instead of an opioid.

Patients’ fear is a factor that is less often addressed. In a study of 80 patients with chronic pain, 32% expressed concerns about addiction, 16% about withdrawal, and 12% of the stigma of opioid use ( ). Fear of tolerance, more than of addiction, was considered a factor in increased pain intensity reporting ( ). In addition, patients’ attitudes toward pain and suffering, knowledge about resources available for pain relief, and intention to use them can be quite variable ( ).

Fear of regulatory scrutiny, added to the lack of detailed knowledge about often complex laws governing the use of opioids, continues to perpetuate underprescription ( ). Laws and regulations governing the production and distribution of opioids have been established by international treaties and national and state laws and regulations. The Single Convention on Narcotic Drugs, adopted in 1961 and amended in 1972, is the international treaty that regulates the production, manufacture, import, export, and distribution of “narcotics” for medical use (International Narcotics Control Board [ ). Although its emphasis is on combating illicit drug trafficking and it is not intended to reduce medical use of opioids, perception and practical implications have created an invisible barrier.

On a professional level, the negative attitudes of regulatory bodies toward the use of opioids for chronic pain, in particular in patients with pain and substance abuse, and these bodies’ inability to distinguish tolerance, physical dependence, and addiction have been reported to influence the initiation of disciplinary action ( ). The possibility of losing a license to practice or becoming the object of criminal scrutiny is very low, but the fear of this has a disproportionate influence on opioid use in many countries ( ). The elaborate media coverage of single cases has an amplifying effect.

The organizational network to obtain opioids for clinical use is highly variable between countries and also within a hospital. National health authorities are expected to report estimated opioid requirements annually and imports and exports quarterly ( ). Similar reporting of consumption and estimates at the level of national, state, and regional health authorities down to individual pharmacies can contribute to periodic shortages ( ). Fifty-two percent of palliative care experts listed pharmacies as a barrier because of problems such as no stock of medication, restrictive hours, and pharmacists’ objection to opioids ( ). Multiple copy prescriptions, restrictive maximum validity of prescriptions, and time limits on dispensing periods may further impede patient access.

Economic barriers should not be underestimated. Lack of provision in public health care systems, insufficient or non-existent insurance coverage, and unfair reimbursement policies for health care, including prescription drugs, medical equipment, and professional services, inhibit access to acute and chronic pain management. Lack of insurance coverage was the most frequent barrier reported by palliative care experts and occurred in 42.9% of cases ( ). Fifty-seven percent of executives of insurance companies did not consider palliative care as an issue of their concern ( ). Although opioids are fortunately relatively cheap pharmacological agents, the cost associated with heavy regulations for their dispensation and the cost of “fee for service” can increase their overall cost. Furthermore, expensive delivery systems such as slow-release preparations and transdermal patches can make even cheap raw substances expensive and often unaffordable preparations, particularly in developing countries.

Despite these barriers, global consumption of morphine increased rapidly over the period between 1982 and 2001, primarily driven by the WHO Cancer Pain Relief Initiative (1986, 1996). Consumption increased almost fourfold in 10 years from 2.4 tons in 1983 to 10 tons in 1992 and then doubled again, reaching 20.3 tons in 1999 ( ). Similar trends of increase in consumption have also been reported for codeine, oxycodone, dihydrocodeine, dextropropoxyphene, fentanyl, methadone, and tilidine. In the past decade, overall opioid consumption worldwide increased again by more than two and a half times ( ). It is of concern, however, that the 10-fold increase in worldwide morphine consumption resulted mainly from use in a few developed countries. In 2008, Australia, Canada, New Zealand, the United States, and the member states of the European Union together accounted for more than 96% of the global consumption of fentanyl, 90% of the global consumption of morphine, and 98% of the global consumption of oxycodone ( ).

The disparity in the use of opioids between countries is now so extreme that the more liberal approach to opioids in some countries has resulted in increased neurotoxicity in cancer patients ( ) and inappropriate opioid use in patients with chronic pain of non-malignant origin ( ). Contrary to past experiences ( ), the dramatically increased use of opioids in a few selected countries has now led to increased misuse and abuse of prescription opioids in these countries ( ). In contrast, access to opioids for pain relief remains severely restricted in about 150 countries ( ).

Clinical Aspects of Various Opioid Analgesics

Traditionally, opioids have been classified as weak and strong opioids. This classification was reinforced by the ). However, the terms weak and strong are relative rather than absolute; some “weak” opioids, when given in adequate amounts, can have the same therapeutic effect as “strong” opioids. Furthermore, the classification is rather arbitrary and not based on the pharmacodynamic properties of the various compounds. However, it is useful at least as an educational tool ( ) and facilitates the introduction of opioids into pain management by initially using weak opioids, which are less “threatening” in opiophobic environments and usually more easily available ( ).

Structural classifications of opioids based on their chemical properties categorize them as derivatives of morphinans, phenylpiperidine esters, and diphenylpropylamines. This classification has limited usefulness for clinical purposes. Functional classifications, a more practical system, group opioids according to their intrinsic activity as full agonists, partial agonists, antagonists, or mixed agonist–antagonists ( Table 31-1 ). These properties and the receptor affinity of opioids for the various receptor types permit predictions on clinical effects; more details of basic pharmacology are outlined in the previous chapter.

Table 31-1

Classification of Opioids

WORLD HEALTH ORGANIZATION	FUNCTIONAL
Weak Opioids Codeine Dihydrocodeine Dextropropoxyphene Tramadol Strong Opioids Morphine Methadone Fentanyl Hydromorphone Pethidine Oxycodone Buprenorphine Levorphanol Dextromoramide	Full Agonists Morphine Fentanyl Hydromorphone Codeine Methadone Tramadol Pethidine Partial Agonists Buprenorphine Pentazocine Butorphanol Agonists–Antagonists Nalbuphine Nalorphine Full Antagonists Naloxone Naltrexone Methylnaltrexone Alvimopan (ADL 8-2698)

Weak Opioids

Codeine Phosphate

Codeine is a naturally occurring alkaloid of opium and internationally the standard weak opioid ( ). It is metabolized in the liver primarily by glucuronidation, N -demethylation, and O -demethylation. The latter process via cytochrome P450 2D6 is responsible for the transformation to morphine (2–10% of the codeine dose) ( ), the analgesic metabolite of codeine, which itself is devoid of analgesic properties. This limits the clinical usefulness of codeine because around 9% of Caucasians are deficient in this isoenzyme and derive no analgesic benefit from codeine ( ). On the other hand, some people are ultrarapid metabolizers who exhibit high morphine levels after the intake of codeine ( ); the proportion of such metabolizers depends on ethnicity, with up to 29% of some Middle Eastern and North African populations but only 0.5% of some Asian populations being affected. This allele poses a risk to breastfed newborns, who can be exposed to potentially life-threatening morphine levels ( ).

The oral bioavailability of codeine phosphate is variable and the duration of action of an oral dose is 4–6 hours. It is commonly used in doses of 30–120 mg every 4 hours. Codeine, 60 mg, is a very poor analgesic by itself, with a combined number needed to treat (NNT) of 12 for at least 50% pain relief ( ). However, codeine improves the analgesic efficacy of non-opioids; with the addition of 60 mg codeine, the NNT of 1000 mg paracetamol improves from 3.8 to 2.2 and its duration of analgesia is extended ( ). Constipation is a predominant adverse effect of codeine.

Dihydrocodeine

The analgesic effect of this semisynthetic derivative of codeine is independent of metabolization to dihydromorphine ( ). Its analgesic efficacy is similar to that of codeine, with an NNT of 8.1 for 30 mg; however, on its own, dihydrocodeine is still inferior to ibuprofen, 200 mg, or diclofenac, 50 mg ( ). An advantage over codeine from a practical point of view, particularly with long-term therapy, is its availability as a slow-release preparation for use every 12 hours.

Dextropropoxyphene

Dextropropoxyphene is a synthetic opioid that is structurally related to methadone. It is used orally, but despite good oral absorption, it exhibits unpredictable oral bioavailability because of high but saturable first-pass metabolism ( ). It is metabolized in the liver by demethylation to the active metabolite norpropoxyphene, which has low opioid activity but may cause convulsions.

Because of its long duration of action, doses of 50–100 mg are given every 6–8 hours. On a per-milligram basis, dextropropoxyphene is a similarly poor analgesic as codeine, with an NNT of 7.7 for 65 mg and 2.8 for 130 mg, and again improves the analgesia of non-opioids ( ).

In addition to common opioid side effects, confusion, hallucinations, and accumulation leading to convulsions are problems, especially with high doses and in the elderly, where its half-life can be very prolonged. These problems and the risk for prolongation of the QT interval leading to torsades de pointes and cardiac arrest have resulted in withdrawal of dextropropoxyphene from the market in Europe ( ) and discouragement of its use in other countries ( ).

Tramadol

Tramadol is not an opioid in the classic meaning of the term, but it is commonly referred to as an atypical centrally acting analgesic because of its combined effects as an opioid agonist and a monoaminergic drug ( ). However, it is listed as a weak opioid by the , and its specific effect and adverse effect profile makes it possibly the most useful of these drugs. Only in recent years has it become available in nearly all countries, although it has been used for decades in a number of European, Asian, and Latin American countries.

Oral tramadol has high bioavailability in the range of 80–90% and dose-dependent analgesic efficacy, with combined NNTs of 8.5 for 50 mg, 5.3 for 75 mg, 4.8 for 100 mg, and 2.9 for 150 mg (McQuay and Moore 1998). Parenteral administration shows equianalgesic efficacy to pethidine on a milligram-per-milligram basis, and 10 mg of parenteral tramadol matches around 1 mg of morphine ( ). Because of its better oral bioavailability, this ratio becomes 5:1 with oral administration. Despite being classified as a weak opioid, tramadol may even be effective in the treatment of severe pain, with fewer side effects than morphine ( ; ). Tramadol has good efficacy for neuropathic pain ( ) and fibromyalgia ( ).

Metabolism to O -desmethyltramadol (M-1) contributes to its opioid-like analgesic effect and is affected by variability in cytochrome P450 2D6 activity ( ). The current recommended dose limits of 600 mg/day restrict its efficacy in relieving severe pain and lead to a change to morphine ( ); however, the dose limit is a regulatory issue only and unsupported by data ( ).

Synergy of its multiple modes of action for analgesia, but not for adverse effects, explains the adverse effect profile of tramadol being different from that of conventional opioids. The risk for respiratory depression is significantly lower at equianalgesic doses ( ); the risk for potentially fatal respiratory depression is minimal and possibly limited to patients with severe renal failure ( ) or very high overdose ( ). In addition, the incidence and severity of constipation are reduced ( ). Last but not least, tramadol has very low abuse potential, with reported rates of addiction and physical dependence of less than 1 in 100,000 patients exposed ( ). However, nausea and vomiting occur with this drug at the same rate as with other opioids and are the most frequently reported side effects ( ).

Strong Opioids

Morphine

Morphine is the “gold standard” of opioid therapy and has until recently been the most commonly used opioid worldwide. It is available in a wide range of preparations via multiple routes of administration, including immediate- and sustained-release preparations in the form of elixir, suspension, tablets, and capsules, as well as preparations for epidural and intrathecal use. Although oral morphine is fully absorbed, it has limited and quite variable oral bioavailability of between 10 and 45% as a result of extensive first-pass metabolism ( ). Because of this phenomenon, there is large interpatient variability in morphine pharmacokinetics, and dosages need to be determined on an individual basis by titration to pain relief. The situation is further complicated by morphine metabolites. Particularly with long-term use, the active metabolite morphine-6-glucuronide (M6G) contributes to analgesia ( ), whereas morphine-3-glucuronide (M3G) causes adverse effects such as neurotoxicity ( ). Individual factors, including renal function, determine the ratio between M6G and M3G and make management more complex ( ); morphine should be avoided in patients with renal impairment because M6G accumulates and can lead to respiratory depression ( ).

For long-term therapy, controlled-release preparations are available either as film-coated tablets with a matrix of active drug and an inactive core or as capsules containing a large number of polymer-coated pellets, each designed to release morphine at different rates. Comparisons between the two principles show little difference in efficacy or side effects, although intake of capsules every 24 hours has been shown to be associated with less fluctuation in plasma levels than matrix tablets taken every 12 hours ( ). Furthermore, the 24-hour dosage of capsules has advantages in ease of administration and patient acceptability ( ). A controlled-release suspension is also widely available. It is important to consider that controlled-release morphine relies on slow absorption from the gastrointestinal tract, thereby limiting its efficacy in patients with “short bowel” syndrome and in those losing their tablets early after intake because of vomiting or severe diarrhea.

The NNT for 10 mg of morphine injected intramuscularly for combined postoperative pain is 2.9, and a further dose increase improves this efficacy (McQuay and Moore 1998). The number needed to harm (NNH) for minor adverse effects in the same assessment was 9.1.

Oxycodone

Oxycodone (14-hydroxy-7,8-dihydrocodeinone) is a semisynthetic derivative of thebaine and has recently replaced morphine and then tramadol as the most used opioid worldwide. The reason for this rise in use might be avoidance of the term “morphine” in its name, thus making it more appealing to “opiophobic” health care professionals and the public, and good marketing strategies, as well as real pharmacological advantages ( ). It exhibits higher oral bioavailability than morphine does (>60%) and has only metabolites with clinically irrelevant effects ( ), in addition to being available in a wide range of oral and parenteral preparations.

Its analgesic efficacy is comparable to that of morphine, with a median oxycodone–morphine dose ratio of 1:1.5 ( ). Oxycodone has been widely studied for use in neuropathic pain states and was found to have an NNT of 2.5 for this indication, comparable to that of tricyclic antidepressants ( ). Furthermore, oxycodone has agonistic effects on the κ receptor, which might explain its better efficacy for visceral pain than other opioids ( ).

Though not observed consistently, some data indicate a lower rate of hallucinations and itch with oxycodone than with morphine ( ). The fixed combination of slow-release oxycodone and slow-release naloxone is now registered in many markets; it shows reduced constipation without impairing analgesia and causing withdrawal ( ).

Methadone

Methadone is a synthetic opioid that became the maintenance drug for opioid addiction worldwide because of its good oral bioavailability (60–95%), high potency, and long duration of action. However, these properties, its lack of active metabolites, its low cost, and its additional effects as an N -methyl- d -aspartate (NMDA) receptor antagonist and serotonin reuptake inhibitor have led to its increasing use for the treatment of cancer and chronic pain ( ). Other advantages are that hepatic impairment and renal impairment do not influence clearance of methadone significantly ( ). However, the stigma of being a compound for treatment of drug abuse is often a barrier to analgesic use ( ).

Even though its long half-life as a result of redistribution facilitates long-term treatment of pain, it also means that a steady-state plasma concentration may not be reached for 10 days, thus making simple dosing guidelines unachievable. The need for careful and individual determination of dose and dosing interval is further emphasized by the variable and unpredictable variation in half-life from 8–80 hours, which increases the risk for accumulation ( ). Consequently, a widely used titration scheme relies on a patient-controlled approach ( ).

The potency of methadone in comparison to morphine has possibly been underestimated until recently ( ): although previous tables gave a ratio of 1:1–4, the calculated median ratio for patients taking a stable dose was 1:11.2, but with a range from 1:4.4–16.4 and a dose-dependent increase in this ratio ( ). Methadone is used successfully in opioid rotation and causes fewer adverse effects when replacing morphine ( ), and various rotation schemes have been suggested ( ). In particular, it is effective for neuropathic pain states and opioid-induced allodynia and hyperalgesia ( ). Metabolism is via the cytochrome P450 group of enzymes and is thereby increased by inducers such as carbamazepine and reduced by others, including some antiretroviral agents and grapefruit juice ( ). The use of methadone may prolong the QTc interval ( ); this is claimed to not usually be serious, but cases of torsades de pointes cardiac arrest have been reported to the Food and Drug Administration ( ).

Fentanyl

Fentanyl is a potent μ agonist that was initially developed specifically for intravenous anesthetic use; it has high potency, a rapid onset of action, and a short duration of action. It then became an interesting choice in the perioperative period (e.g., by patient-controlled analgesia [PCA]) but has gained an additional new role in cancer and chronic pain management after transdermal and transmucosal preparations became available ( ).

Its high lipid solubility, low molecular weight, and high potency make it an ideal drug for transdermal and transmucosal administration ( ). In systemic availability studies, 92% of the fentanyl dose delivered transdermally reached the systemic circulation as unchanged fentanyl. However, care needs to be taken with the use of these transdermal systems because time from application to peak plasma concentration is 12–24 hours and a residual depot remains in subcutaneous tissue for about 24 hours after removal of the patch. In patients with cancer pain ( ) and chronic pain ( ), transdermal fentanyl is preferred over sustained-release morphine and causes less constipation and other adverse effects. A patch for iontophoretic delivery of fentanyl has been developed but had to be withdrawn because of technical difficulty, with corrosion potentially endangering patient safety ( ).

Oral and nasal transmucosal fentanyl citrate offers a unique way of treating breakthrough and incident pain. Preparations include a lozenge, a buccal tablet, films for buccal and sublingual use, and a number of nasal spray designs in various stages of registration and investigation ( ). The preparations show high bioavailability in the range of 50% with a short time to onset of effect and a short duration of action. Despite being indicated only for relief of breakthrough pain in cancer, there is realistic concern about widespread off-label use (90% in the United States) in patients with chronic pain of non-malignant origin and high risk for abuse ( ).

Hydromorphone

Hydromorphone, another semisynthetic opioid, is a hydrogenated ketone analogue of morphine. It is regarded as an effective alternative to morphine for the treatment of moderate to severe pain and is available for oral, parenteral, and rectal use ( ). It is 3–5 times as potent as morphine when given orally and 8.5 times as potent parenterally ( ). Its duration of action is 3–4 hours; slow-release preparations for intake every 24 hours are available in many markets ( ). Hydromorphone-3-glucuronide is a potentially neurotoxic metabolite that is retained in patients with renal failure ( ).

Diamorphine

Diamorphine is 3,6-diacetyl morphine and is commonly known as heroin. It is a lipophilic prodrug of the active metabolite 6-monoacetylmorphine, which is further metabolized to morphine. It is well absorbed by all routes and crosses the blood–brain barrier easily because of its greater lipid solubility, thus explaining its popularity among abusers. Consequently, it is available as a therapeutic agent only in very few countries; it has no obvious advantages over morphine by the systemic route ( ). However, its physicochemical benefits are advantageous for neuraxial administration ( ).

Buprenorphine

Buprenorphine is another semisynthetic derivative of thebaine. It is a partial agonist at the μ receptor and a κ antagonist with high receptor affinity to both, but a weak δ agonist. Its clinical application has recently undergone a renaissance because of increased use of the compound for abuse substitution with high-dose use and registration of transdermal preparations in the lower dose range ( ). The current literature is confusing because there are wide variations in the pharmacology of different species and increased use of high doses in the 2–32-mg range, previously regarded as not being useful ( ). The role of buprenorphine in the treatment of cancer and chronic pain has become established in recent times ( ); advantages are increased safety with regard to respiratory depression and immune suppression, reduced rate of constipation, and no accumulation in patients with impaired renal function.

Oral administration results in high first-pass metabolism, which can be overcome by sublingual or transdermal administration. Sublingually, buprenorphine has a relatively rapid onset of 30 minutes with a long duration of analgesia of 6–9 hours. Transdermal patches deliver 5–70 μg/hr for 4–7 days ( ).

Pethidine (Meperidine)

Pethidine is a synthetic opioid that is still widely used for traditional reasons despite its multiple disadvantages. It is a complex drug with additional anticholinergic effects because of its structural similarity to atropine and local anesthetic action. These effects have resulted in the claim of superior effect for colicky pain, but this could not be substantiated in clinical trials (Connor et al 2000). Problems are its high lipophilicity, which seems to induce typical drug-seeking behavior. A metabolite, norpethidine, is a neurotoxic central nervous system (CNS) stimulant that causes agitation, tremors, myoclonus, and generalized seizures, particularly in high doses, with prolonged use, or in patients with renal failure ( ).

Pethidine is 8–10 times less potent than morphine and exhibits poor variable oral absorption with a short duration of action in the range of 2–3 hours. For all these reasons it is recommended that pethidine not be used if alternatives are available ( ); it is reassuring that its medical use is declining significantly ( ), in line with advice against its use ( ).

Tapentadol

Tapentadol is a new opioid compound that was recently registered in the United States and Europe. It is a potent μ agonist but also a noradrenaline reuptake inhibitor ( ). This dual mechanism of action seems to lead to reduced adverse gastrointestinal effects (nausea, vomiting, constipation) in comparison to conventional opioids; it might also lead to improved efficacy in neuropathic pain states ( ).

Other Strong Opioids

Multiple other strong opioids are available in some countries; however, the international literature on these compounds is limited. Dextromoramide is a short-acting opioid that may be useful as a rescue analgesic for patients intolerant of morphine, but it is unlikely to be of use for chronic pain ( ).

Levorphanol, like methadone, has a long half-life and tendency to accumulate and cause excessive sedation with repeated doses; it is usually started in oral doses of 2 mg every 6 hours ( ).

Routes of Administration for Opioids

Opioids are administered in routine clinical practice via a wide range of routes. Each has certain advantages and disadvantages, as well as indications and contraindications. Detailed knowledge of the features of each route of administration, as well as the suitability of specific compounds via this route, is necessary to treat pain effectively with opioids. Switching between routes of administration may become necessary over the course of a painful disease process and requires knowledge of potency ratios and other peculiarities of this process; in certain situations, a change of compound might be required in parallel because not all opioids are available via all routes of administration.

Oral

The oral route is the preferred route of administration in most clinical situations because of ease of access, good tolerability, ability to self-administer, and cost of preparations; it is the recommended universal route of administration by the . Most opioids are available as oral formulations, and sustained-release preparations have made the oral route even more convenient for long-term management of pain. Oral bioavailability is the major factor to consider here; mean data are listed in Table 31-2 , but high intra- and interindividual variability needs to be considered. Oral preparations via the nasogastric route may be used in patients who are unconscious, uncooperative, or unable to swallow medications.

Table 31-2

Approximate Oral Bioavailability of Commonly Used Opioids

Data compiled from multiple sources.

OPIOID	ORAL BIOAVAILABILITY
Hydromorphone	20%
Morphine	30%
Diamorphine	30%
Pethidine (meperidine)	30%
Codeine	60%
Oxycodone	60%
Levorphanol	70%
Tramadol	80%
Methadone	80%

Rectal

The rectal route is a common alternative to the oral route in patients with nausea, vomiting, and other reasons to abandon oral administration of opioids. Absorption occurs via both the systemic and portal circulation, the latter reducing the degree of first-pass metabolism but also leading to wider variability in bioavailability in comparison to oral use. Most experience exists with rectal morphine for cancer pain ( ).

Sublingual

This route avoids hepatic first-pass metabolism; absorption is best for drugs with high lipid solubility, which are un-ionized in the alkaline medium of the mouth. Accordingly, the bioavailability of morphine via this route is only 18% as opposed to 51% for fentanyl and 34% for methadone ( ), and morphine therefore has very limited efficacy via this route ( ).

Fentanyl citrate in various preparations for transmucosal application (lozenges, buccal tablets, films) ( ) and sublingual buprenorphine ( ) are the main compounds used via the sublingual route.

Intranasal

Though popular for illicit use, intranasal administration currently plays only a limited clinical role. This route also avoids first-pass metabolism, and reliable absorption depends on the lipid solubility of the drug. Studies on bioavailability are available for many drugs and suggest a promising potential for this underused route of administration ( ).

Butorphanol is available as a metered spray ( ). Fentanyl has also been used intranasally, has shown pharmacokinetics similar to intravenous administration, and is currently under investigation for the treatment of breakthrough, acute postoperative, and post-trauma pain ( ).

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