Opioids
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.
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 World Health Organization (WHO) (1986, 1996). The major barriers are insufficient knowledge, inappropriate attitudes, regulatory and organizational issues, and economics (Anderson 2010). “Opiophobia” (Morgan 1985, Zenz and Willweber-Strumpf 1993), 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 (Zenz and Willweber-Strumpf 1993).
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) (McQuay 1999). 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 (Joranson and Gilson 2001).
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 (Edwards et al 2001). 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 (Casarett et al 2002). Fear of tolerance, more than of addiction, was considered a factor in increased pain intensity reporting (Paice et al 1998). In addition, patients’ attitudes toward pain and suffering, knowledge about resources available for pain relief, and intention to use them can be quite variable (Fins 1997).
Fear of regulatory scrutiny, added to the lack of detailed knowledge about often complex laws governing the use of opioids, continues to perpetuate underprescription (Rothstein et al 1998). 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 [INCB] 1972). 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 (Gilson and Joranson 2001). 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 (Goldenbaum et al 2008). 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 (INCB 1972). 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 (INCB 2010). 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 (Gee and Fins 2003). 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 (Gee and Fins 2003). Fifty-seven percent of executives of insurance companies did not consider palliative care as an issue of their concern (Hoffmann 1998). 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 (INCB 2003). 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 (INCB 2010). 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 (INCB 2010).
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 (Daeninck and Bruera 1999) and inappropriate opioid use in patients with chronic pain of non-malignant origin (Streltzer et al 2009). Contrary to past experiences (Costa e Silva 2002), 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 (Gilson and Kreis 2009). In contrast, access to opioids for pain relief remains severely restricted in about 150 countries (Anderson 2010).
Traditionally, opioids have been classified as weak and strong opioids. This classification was reinforced by the WHO analgesic guidelines (1986, 1996). 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 (Grond and Meuser 1998) 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 (Freynhagen et al 1994).
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
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) |
Codeine is a naturally occurring alkaloid of opium and internationally the standard weak opioid (World Health Organization 1996). 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) (Lotsch 2005), 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 (Stamer and Stuber 2007b). On the other hand, some people are ultrarapid metabolizers who exhibit high morphine levels after the intake of codeine (Kirchheiner et al 2007); 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 (Madadi et al 2009).
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 (Derry et al 2010). 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 (Toms et al 2009). Constipation is a predominant adverse effect of codeine.
The analgesic effect of this semisynthetic derivative of codeine is independent of metabolization to dihydromorphine (Leppert 2010a). 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 (Edwards et al 2000). 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 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 (Collins et al 1998). 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 (Collins et al 1998).
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 (Bateman and Sandilands 2009) and discouragement of its use in other countries (Barkin et al 2006).
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 (Bamigbade et al 1997). However, it is listed as a weak opioid by the WHO (1996), 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 (Scott and Perry 2000). 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 (Wilder-Smith et al 1994, 1999; Grond et al 1999). Tramadol has good efficacy for neuropathic pain (Hollingshead et al 2006) and fibromyalgia (Carville et al 2008).
Metabolism to O-desmethyltramadol (M-1) contributes to its opioid-like analgesic effect and is affected by variability in cytochrome P450 2D6 activity (Kirchheiner et al 2007, Stamer and Stuber 2007b). The current recommended dose limits of 600 mg/day restrict its efficacy in relieving severe pain and lead to a change to morphine (Radbruch et al 1996); however, the dose limit is a regulatory issue only and unsupported by data (Schug 2003).
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 (Scott and Perry 2000); the risk for potentially fatal respiratory depression is minimal and possibly limited to patients with severe renal failure (Barnung et al 1997) or very high overdose (Clarot et al 2003). In addition, the incidence and severity of constipation are reduced (Wilder-Smith et al 1999). 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 (Cicero et al 2005). However, nausea and vomiting occur with this drug at the same rate as with other opioids and are the most frequently reported side effects (Radbruch et al 1996).
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 (Gourlay et al 1986). 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 (Hanna et al 1990), whereas morphine-3-glucuronide (M3G) causes adverse effects such as neurotoxicity (Lotsch 2005). Individual factors, including renal function, determine the ratio between M6G and M3G and make management more complex (Glare and Walsh 1991); morphine should be avoided in patients with renal impairment because M6G accumulates and can lead to respiratory depression (Schug and Morgan 2004).
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 (Gourlay et al 1997). Furthermore, the 24-hour dosage of capsules has advantages in ease of administration and patient acceptability (Broomhead et al 1997). 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 (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 (Rischitelli and Karbowicz 2002). It exhibits higher oral bioavailability than morphine does (>60%) and has only metabolites with clinically irrelevant effects (Riley et al 2008), 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 (Bruera et al 1998). 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 (Sindrup and Jensen 1999). Furthermore, oxycodone has agonistic effects on the κ receptor, which might explain its better efficacy for visceral pain than other opioids (Riley et al 2008).
Though not observed consistently, some data indicate a lower rate of hallucinations and itch with oxycodone than with morphine (Bruera et al 1998). 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 (Mueller-Lissner 2010).
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 (Garrido and Troconiz 1999, Bruera and Sweeney 2002). Other advantages are that hepatic impairment and renal impairment do not influence clearance of methadone significantly (Novick et al 1981). However, the stigma of being a compound for treatment of drug abuse is often a barrier to analgesic use (Shah and Diwan 2010).
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 (Gourlay et al 1986). Consequently, a widely used titration scheme relies on a patient-controlled approach (Sawe et al 1981).
The potency of methadone in comparison to morphine has possibly been underestimated until recently (Bruera et al 1996): 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 (Lawlor et al 1998). Methadone is used successfully in opioid rotation and causes fewer adverse effects when replacing morphine (Bruera et al 1996), and various rotation schemes have been suggested (Weschules and Bain 2008). In particular, it is effective for neuropathic pain states and opioid-induced allodynia and hyperalgesia (Bruera and Sweeney 2002). 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 (Weschules and Bain 2008). The use of methadone may prolong the QTc interval (Cruciani et al 2005); 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 (Pearson and Woosley 2005).
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 (Grape et al 2010).
Its high lipid solubility, low molecular weight, and high potency make it an ideal drug for transdermal and transmucosal administration (Grape et al 2010). 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 (Wong et al 1997) and chronic pain (Allan et al 2001), 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 (Grape et al 2010).
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 (Grape et al 2010). 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 (O’Connor 2008).
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 (Quigley and Wiffen 2003). It is 3–5 times as potent as morphine when given orally and 8.5 times as potent parenterally (Sarhill et al 2001). Its duration of action is 3–4 hours; slow-release preparations for intake every 24 hours are available in many markets (Wallace et al 2007). Hydromorphone-3-glucuronide is a potentially neurotoxic metabolite that is retained in patients with renal failure (Murray and Hagen 2005).
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 (Sawynok 1986). However, its physicochemical benefits are advantageous for neuraxial administration (Green et al 2007).
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 (Heit and Gourlay 2008). 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 (Cowan 2003). The role of buprenorphine in the treatment of cancer and chronic pain has become established in recent times (Pergolizzi et al 2009); 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 (Sittl 2006).
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 (Armstrong and Bersten 1986).
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 (World Health Organization 1996); it is reassuring that its medical use is declining significantly (Joranson et al 2000), in line with advice against its use (Latta et al 2002).
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 (Sloan 2010). 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 (Prommer 2010).
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 (World Health Organization 1996).
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 (World Health Organization 1996).
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.
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 WHO (1996). 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
OPIOID |
ORAL BIOAVAILABILITY |
| Hydromorphone | 20% |
| Morphine | 30% |
| Diamorphine | 30% |
| Pethidine (meperidine) | 30% |
| Codeine | 60% |
| Oxycodone | 60% |
| Levorphanol | 70% |
| Tramadol | 80% |
| Methadone | 80% |
Data compiled from multiple sources.
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 (Wilkinson et al 1992, DeConno et al 1995).
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 (Weinberg et al 1988), and morphine therefore has very limited efficacy via this route (Coluzz, 1998).
Fentanyl citrate in various preparations for transmucosal application (lozenges, buccal tablets, films) (Grape et al 2010) and sublingual buprenorphine (Bono and Cuffari 1997) are the main compounds used via the sublingual route.
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 (Dale et al 2002).
Butorphanol is available as a metered spray (Dale et al 2002). 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 (Grape et al 2010).
Inhalation is also possibly an underused route for opioids. Inhaled fentanyl was effective with minimal adverse effects in patients with postoperative pain (Worsley et al 1990). Similarly, morphine by inhalation showed 55% bioavailability and good effect (Dershwitz et al 2000).
Opioids need to be highly lipid soluble and have low molecular weight and high potency to permit transdermal uptake of clinically effective amounts. The pharmacokinetic profile of slow attainment of steady-state concentrations, stable maintenance of these concentrations, and slow decline after removal of the patch make transdermal therapeutic systems unsuitable for acute pain and fluctuating chronic pain requiring frequent dose adjustments.
Fentanyl (Allan et al 2001, Grape et al 2010) and more recently buprenorphine (Sittl et al 2003) are the two transdermal compounds in current clinical use.
Iontophoresis is a modification of the transdermal administration of drugs that is achieved by applying electric current to deliver drugs in an ionized state. The potential advantages of iontophoresis over simple transdermal administration are on-demand function, rapid achievement of plasma concentrations, and the ability to vary the delivery rate. A very promising iontophoretic patch for fentanyl with a patient-controlled function was registered and available, but its registration was suspended in view of technical difficulties with corrosion (Grape et al 2010).
This is the parenteral route of choice for cancer pain management because it enables easy and safe management of patients unable to take oral medication in their own home (Nelson et al 1997). Drugs are administered through a subcutaneous needle or catheter either as intermittent injections or via syringe drivers. The rate of absorption is slow and constant, thus providing a smooth, sustained effect. Drugs given by this route should be soluble, locally non-irritating, and well absorbed from subcutaneous tissue. The overall amount of fluid should not exceed 5 mL/hr to avoid patient discomfort (Derby et al 1998).
Drugs commonly used by this route are morphine, fentanyl, and hydromorphone. Methadone and pethidine seem more likely to cause inflammatory reactions and hence are not recommended (Bruera et al 1991).
Intravenous administration allows rapid and reliable establishment of analgesia. It is most useful in the acute care setting and is increasingly being used with PCA (Momeni et al 2006). However, it is not the parenteral route of choice for chronic and cancer pain because intravenous access is more difficult to maintain than subcutaneous access in the long term.
Historically, this was the preferred parenteral route of administration for opioids (Schug 1999). However, it does not convey clinically relevant pharmacokinetic advantages over oral or subcutaneous administration (Austin et al 1980), which are perceived as being more acceptable by patients and less invasive with reduced risk for infection and nerve injury. It is also not appropriate for urgent analgesia, for which intravenous administration is much faster. Intramuscular opioid administration should be discouraged and replaced by oral, subcutaneous, or intravenous administration, depending on the indication and required speed of onset.
Drugs administered by the epidural and spinal route gain access to cerebrospinal fluid and then the substantia gelatinosa of the dorsal horn to interact with spinal opioid receptors, but supraspinal effects are also exerted by rostral spread and systemic absorption (McCartney and Chambers 2000). Neuraxial opioids are used for the treatment of acute, cancer, and chronic pain and during childbirth (see Chapter 55) alone or in combination with local anesthetics, clonidine, and various other, often still experimental, agents (Schug et al 2006).
For acute pain, they are most useful in low doses as adjuncts to local anesthetics and are administered mainly epidurally (see Chapters 37 and 46). The indication for neuraxial opioids for cancer and chronic pain is primarily the presence of intolerable side effects or inadequate analgesia during systemic opioid administration (see also Chapter 75). However, pain unresponsive to opioids should be excluded, appropriate co-analgesics tried, and opioid rotation attempted. In view of the invasiveness of this approach, the expertise required, the infrastructure necessary to provide ongoing care, and the considerable cost, the indication for this approach should be made with care (Ghafoor et al 2007). Devices for delivery range from simple percutaneous catheters, to more complex totally implanted catheters with injection ports, to implanted pump system for infusion. The choice of technique depends on staff experience, life expectancy of patients, and cost.
The choice of opioids used is influenced primarily by the physicochemical properties of the agents (Bernards 2004); high water solubility, as in the case with morphine, results in a long duration of action, extensive dermatomal spread, but also more rostral spread with more central adverse effects. Lipophilic agents such as fentanyl bind more readily at the site of injection and result in limited dermatomal and rostral spread but have high systemic absorption if injected epidurally. For morphine, the suggested dose reduction from oral to epidural administration is 2–5% and from oral to intrathecal is 0.5–1% of the daily oral dose.
Opioids have multiple adverse effects (Box 31-1). Most of these effects are mediated through the opioid receptor and hence intrinsically linked to the mechanism of action of opioids (Schug et al 1992, Lawlor and Bruera 1998, Benyamin et al 2008). However, the clinical relevance of these adverse effects varies widely for a number of reasons. First, the “dual pharmacology” of opioids, referred to previously, explains differences in effects between patients in pain and pain-free individuals such as volunteers or abusers (McQuay 1999); thus studies in volunteers may not reflect their effects in patients with pain. Second, the adverse effects are dose related, and comparisons between opioids need to be made at equianalgesic doses. Furthermore, the route of administration and the speed of administration influence the effects. Last but not least, the effects of opioids show wide-ranging inter- and intra-individual variability, depending among other factors on progression of the disease, increase in nociception, drug interactions, and emotional status.
Opioids cause a dose-dependent depression of all phases of respiratory activity (Schug et al 1992). Respiratory depression is the most common cause of death related to opioid overdose. Sedation, sleep, or mental clouding always accompanies clinically significant respiratory depression.
Opioid-naïve patients, patients at the extremes of age, and those with pre-existing respiratory disease are more at risk for respiratory depression. Tolerance to respiratory depression develops rapidly and is reversible. Buprenorphine (Pergolizzi et al 2009) and tramadol (Scott and Perry 2000) offer reduced risk for respiratory depression.
It has been postulated that the respiratory center also receives nociceptive input. Thus, pain acts as a physiological antagonist to respiratory depression (Hanks and Twycross 1984). Patients stable on long-term, high-dose opioid therapy are susceptible to the development of respiratory depression when the pain is decreased because of surgical or neurolytic procedures. The clinical message here is to constantly titrate opioids against pain.
In addition, opioids cause direct depression of the cough center in the medulla (Schug et al 1992). This is an indication for the use of opioids (codeine and diamorphine in particular) but is a potential disadvantage in the perioperative period. However, this effect should not limit the use of opioids in this situation because pain itself may suppress coughing.
Nausea and vomiting are common adverse effects of opioids and the ones most disliked by patients. Up to two-thirds of patients experience these adverse effects during initiation of opioid therapy. They are the result of direct stimulation of the chemoreceptor trigger zone in the area postrema of the medulla. The effect is dose related and subject to the rapid development of tolerance (i.e., much more common at the initiation of therapy). Prescribing regular antiemetics during the initiation of opioid therapy is a useful approach. Persistent nausea despite appropriate antiemetic use warrants opioid rotation or change in the route of administration. The new opioid tapentadol shows reduced rates of nausea and vomiting, possibly as a result of a dual mechanism of action (Sloan 2010).
Constipation is the most common and bothersome adverse effect of long-term opioid therapy (Lawlor and Bruera 1998). It is due to decreased peristalsis, decreased intestinal secretions, and increased sphincter tone as a result of peripheral opioid receptor activation. A matter of clinical concern is that tolerance rarely develops (Benyamin et al 2008). Hence laxatives often need to be used continuously during opioid therapy.
Because constipation is a peripheral phenomenon caused by μ-receptor activation in the bowel, peripheral opioid receptor antagonists have recently been used in an attempt to treat or prevent opioid-induced constipation and prolonged paralytic ileus in the perioperative period. Oral naloxone, subcutaneous methylnaltrexone, and alvimopan (ADL 8-2698) are currently used in various settings to reverse opioid-induced bowel dysfunction without compromising analgesia or inducing CNS side effects (McNicol et al 2008, Leppert 2010b).
Opioids inhibit micturition reflexes and increase sphincter tone, thereby resulting in urgency and retention. This side effect is more likely to occur after the neuraxial administration of opioids (Schug et al 1992, Lawlor and Bruera 1998).
Sedation is a common problem, in particular during initiation of opioid therapy. However, tolerance commonly develops rapidly over a week. Interaction with other CNS depressants such as alcohol and benzodiazepines is additive. With persistent sedation, rotation to another opioid may be a management option. If excessive sedation is a problem, reducing the dose by around 20%, more frequent small doses, and the addition of psychostimulant drugs such as methylphenidate and dexamphetamine are other options for management (Bruera et al 1992). However, a randomized controlled trial showed no long-term benefit of dexamphetamine in this case (Auret et al 2009).
Cognitive impairment is of concern for prescribing physicians and patients maintained on high doses of opioids over prolonged periods. Many patients will want to continue to work or more importantly to drive because driving is often associated with independence and freedom. Limiting driving or work is of concern when the goal of therapy is to increase function and quality of life. However, the overall data are reassuring here: a controlled study of patients maintained on stable doses of morphine (mean oral daily dose, 209 mg), when compared with pain-free cancer patients without regular analgesic intake, revealed only slight selective effects on cognitive function related to driving that were considered non-hazardous with regard to driving ability (Vainio et al 1995). Chronic pain patients receiving stable doses of transdermal fentanyl over a 2-week period showed no significant psychomotor or cognitive impairment in comparison to volunteers (Sabatowski et al 2003). Similar findings for transdermal buprenorphine have been published (Dagtekin et al 2007). Seven days after dose adjustment, patients were again able to drive without impairment (Gaertner et al 2008).
It is therefore unreasonable to prohibit driving altogether while patients are taking stable doses of opioids (Byas-Smith et al 2005). It is justifiable to warn all patients in whom opioid therapy is being initiated and patients with dose escalations of more than 20% about cognitive impairment and its potential effect on work and driving. It is also reasonable to suggest to patients that it is their own ongoing responsibility to assess their competence to safely operate a motor vehicle (Lawlor and Bruera 1998) and to base the decision on individual assessment (Sabatowski et al 2010).
Both visual and tactile hallucinations, as well as delirium, have been described in patients taking opioids (Vella-Brincat and Macleod 2007). Delirium may be manifested as a combination of cognitive failure, disturbed sleep, altered level of consciousness, and other psychomotor disturbances. Because of the complexity of its characteristics and diverse etiology, delirium is frequently underdiagnosed, misdiagnosed, and undertreated, thus causing considerable distress to patients and caretakers. Treating physicians need to recognize that agitation and withdrawal in a patient treated with opioids may be manifestations of opioid toxicity but that other causes of neurotoxicity need to be excluded (Box 31-2).
In a study of 93 cases of delirium in 103 advanced cancer patients, opioid toxicity was shown to be independently associated with reversibility of the delirium (Lawlor et al 2000).
Opioids can produce a spectrum of movement abnormalities that include rigidity, myoclonus, and seizures (Benyamin et al 2008). These adverse effects have been reported with both rapid intravenous administration (Viscomi and Bailey 1997) and chronic therapy, in particular at high doses (Lawlor and Bruera 1998). The neurotoxicity of metabolites such as M3G has been blamed for these complications (Smith 2000). Similarly, pethidine is commonly linked to these side effects because of the neurotoxicity of its metabolite norpethidine; this is another reason to reduce use of this compound, particularly in high doses or long-term. Tramadol is another substance that has been claimed to induce idiopathic seizures; however, this impression could not be confirmed in two cohort studies, which showed no increased risk for seizures with tramadol (Jick et al 1998, Gasse et al 2000).
Overall, these adverse effects appear to be dose related in an unpredictable manner; patients with pre-existing epilepsy or taking other seizure threshold–lowering drugs seem to be at an increased risk. Opioid rotation toward compounds with inactive metabolites and use of clonazepam have been reported to be helpful in the treatment of such complications; clonazepam also seems to be the agent of choice to terminate seizures induced by opioids.
Pruritus is an unpleasant side effect of opioids, more often associated with neuraxial opioids. The mechanism of this pruritus is still unclear but it is thought to be due to central and peripheral effects, namely, to μ-receptor activation at the level of the medullary dorsal horn and to histamine release after systemic administration (Reich and Szepietowski 2010). Antihistamines, opioid antagonists, propofol, and ondansetron have been used for treatment. Hydromorphone (Katcher and Walsh 1999) and intranasal butorphanol (Dunteman et al 1996) have been reported to reduce opioid-induced pruritus resistant to antihistamines. Overall, antagonists are the most effective treatment here but can reduce analgesic efficacy (Reich and Szepietowski 2010). Opioid rotation is another treatment option.
With regard to cardiovascular effects, opioids generally produce some hypotension and bradycardia with potential consequences in medically complicated and elderly patients (Smith and Bruckenthal 2010); the exception is pethidine, which causes tachycardia. A major causative component of the hypotension caused by most opioids, in particular, morphine, is most likely histamine release (Schug et al 1992). Pulmonary edema has been reported in patients after very high doses of morphine as a result of increased capillary permeability (Bruera and Miller 1989).
Immune suppression has been linked to μ-receptor agonism (Sacerdote 2008). In postoperative patients with cancer, corresponding with experimental findings (Tsai and Won 2001), morphine resulted in more pronounced and prolonged immune suppression than tramadol did (Sacerdote et al 2000). Similarly, intrathecal morphine has been reported to depress natural killer cell activity in postoperative patients (Yokota et al 2000), whereas buprenorphine has less effect on the immune system (Sacerdote 2008). However, the clinical relevance of these findings has been debated recently (Rittner et al 2010).
Endocrine changes can be a consequence of long-term opioid use (Merza 2010). In long-term opioid users, pituitary axis dysfunction is found on all levels (Rhodin et al 2010); hypogonadism is the most common consequence, but adrenal insufficiency and effects on growth hormone have also been described (Merza 2010). This may lead to reduced libido and erectile dysfunction in men, oligomenorrhea or amenorrhea in women, and bone loss and infertility (Vuong et al 2010). Such dysfunction is reversible by decreasing opioid doses or discontinuing opioid treatment and may otherwise require hormone replacement (Rhodin et al 2010).
Tolerance is defined as the need for increasing doses to maintain a defined pharmacodynamic effect. Opioid tolerance in animals is predominantly of a pharmacodynamic nature, time and dose dependent, receptor specific, and reversible (Collett 1998). Opioid tolerance is characterized by a shortened duration and decreased intensity of effects such as analgesia, euphoria, and CNS depression, as well as a significant increase in the lethal dose.
Under experimental conditions, different opioid effects manifest tolerance at different rates: tolerance to respiratory depression develops quickly and is rapidly reversible. Tolerance to sedation, cognitive effects, and nausea and vomiting develops more slowly. Constipation and miosis are the two receptor-mediated effects for which no tolerance develops (Schug et al 1992).
Tolerance to analgesic effects seems to be irrelevant in clinical practice (Collett 1998). In the acute setting there is no evidence of the development of tolerance, and patients increase their opioid use only in response to increased pain (Chapman and Hill 1989). Similarly, prolonged use of opioids in patients with chronic pain of non-malignant origin (Glynn and Mather 1982) and with cancer pain (Schug et al 1992) was not associated with the development of tolerance to analgesia; patients could be maintained on steady doses of opioids for long periods, and dose increases were needed predominantly in response to increasing pain as a result of increasing nociception from disease progression.
On the basis of these observations, it is strongly recommended that in the case of lack or loss of analgesic effect of opioids, development of pharmacodynamic tolerance should not be assumed automatically (Portenoy 1994); other explanations should be considered along the lines of the possible causes listed in Box 31-3.
In this context, the issue of opioid-induced hyperalgesia (OIH) needs to be addressed. OIH describes the phenomenon that opioid exposure lowers the pain threshold. Although this has been shown conclusively in rodents and pain-free human volunteers receiving opioid infusions, data in all other settings are currently contradictory (Fishbain et al 2009). Overall, some data on chronic pain patients taking opioids and opioid addicts show a different nociceptive profile from those not taking opioids, but the data are inconsistent and may be dependent on external factors such as the modalities tested and opioids used (Bannister and Dickenson 2010). For example, OIH has been observed with the use of very large doses of morphine via various routes of administration (Andersen et al 2003), often accompanied by myoclonus. Here, it seems to respond to discontinuation of morphine and substitution with another opioid (Sjogren et al 1994). This suggests that morphine or its metabolites are the cause of these problems; in view of animal data showing M3G to cause excitation and antalgesic effects, it is assumed to be the cause of these symptoms in humans as well (Sjogren et al 1994, Andersen et al 2003).
Cross-tolerance is defined as the phenomenon that repeated doses of one drug result in the development of tolerance to other drugs in the same category. The development of cross-tolerance to opioids is unpredictable but, according to most data, incomplete (Collett 1998). Incomplete cross-tolerance is one of the arguments in favor of opioid rotation or switch (i.e., sequential change to other opioids in the case of the need for dose escalation of one opioid leading either to incomplete analgesia or unacceptable adverse effects [Vissers et al 2010]). It can lead to restoration of analgesia and a reduction in adverse effects. Obviously, different strong opioids interact with different opioid receptor subtypes or modulate the signaling of one opioid receptor in different ways (Smith 2008). These observations also explain the superior efficacy and reduced adverse effects of combining two opioids such as morphine and oxycodone.
Physical dependence is defined as the occurrence of withdrawal symptoms after the abrupt discontinuation of a drug or the administration of an antagonist (Schug et al 1992). It is a physiological effect of opioids and is expected when opioids are used chronically, but it may also develop acutely, depending on the dose and dosing interval with short-term use. Physical dependence reflects neuroadaptation as a result of changes in opioid receptors and is related to intracellular second-messenger systems in both peripheral and central neurons.
Withdrawal symptoms from opioids are well described (Collett 1998). Yawning, diaphoresis, lacrimation, and tachycardia are the initial manifestations, followed by abdominal cramps, nausea, and vomiting. The symptoms develop rapidly within hours of cessation of opioid therapy, may reach a maximum in 2–3 days, and can last for several days. During this time, tolerance is lost rapidly. Pain is often present and is usually perceived as generalized musculoskeletal pain and abdominal cramps.
Withdrawal symptoms can be a potential inconvenience to patients with genuine loss or a stolen opioid prescription. However, withdrawal has not been a problem clinically in patients maintained on long-term opioid therapy (Buckley et al 1986); in the case of effect of other analgesic modalities or a decision to discontinue opioid medication, withdrawal can be achieved easily by tapering the dose gradually (Schug et al 1992). Because increased sympathetic activity in the CNS is an important cause of withdrawal symptoms, use of clonidine is a useful treatment option.
Addiction, often also commonly called “psychological dependence,” is distinct from physical dependence and tolerance. It is characterized by a behavioral pattern of compulsive drug use resulting in physical, psychological, and social harm. However, the need for a more appropriate definition in the context of opioid intake for pain treatment has been recognized. Such a definition was suggested by Portenoy (1990):
A psychologic and behavioral syndrome characterized by: (1) an intense desire for the drug and overwhelming concern about its continued availability (psychologic dependence); (2) evidence of compulsive drug use (characterized, for example, by unsanctioned dose escalation, continued dosing despite significant side-effects, use of drug to treat symptoms not targeted by therapy, or unapproved use during periods of no symptoms); and/or (3) evidence of one or more of a group of associated behaviors, including manipulation of the treating physician or medical system for obtaining additional drug (altering prescriptions, for example), acquisition of drugs from other medical sources or from a non-medical source, drug hoarding or sales, or unapproved use of other drugs (particularly alcohol or other sedatives/hypnotics) during opioid therapy.
Addiction as a consequence of therapeutic use of opioids in patients with acute pain (Chapman and Hill 1989) and cancer pain is regarded as extremely rare. In a retrospective study of 550 patients with cancer pain treated with long-term opioids, behavior fulfilling the above definition was noted in only one patient (Schug et al 1992). However, the increasing survival times of cancer patients (Starr et al 2008, Passik 2010) and even more so the increasing use of opioids in patients with chronic pain of non-malignant origin seem to have led to more problems recently; in a systematic review of opioid use to treat chronic back pain, the prevalence of current substance abuse was 43% and that of aberrant medication use behavior was up to 24% (Martell et al 2007). These concerning findings have been confirmed in a careful literature review (Hojsted and Sjogren 2007). One reason may be that the prevalence of addiction is increased in patients with pain (Savage 2002).
Whether and how an addictive disorder affects pain and pain management depend on many variables, including the status of the addictive disorder, the duration and quality of recovery if present, medications and the effectiveness of pain treatment, co-existing psychosocial problems, and support (Savage 2002, Ballantyne and LaForge 2007). Thorough physical and psychosocial assessment, including the use of appropriate tools to identify patients at risk, extreme caution, anticipation of problems, and timely intervention by counseling are recommendations for success in this complex setting (Passik and Kirsh 2008). Such careful selection seems to be the recipe for avoiding addiction as a major issue in chronic pain treatment (Watson et al 2010).
Another issue of relevance in this context is pseudo-addiction (Weissman and Haddox 1989). This is behavior perceived by health care professionals as addiction but represents an iatrogenic syndrome of abnormal behavior developing as a direct consequence of inadequate pain management. It is usually triggered by inadequate prescription of analgesics to meet the pain on initial encounter with the health care practitioner. The patient responds to the insufficient treatment by escalation of analgesic demands associated with behavioral changes to convince others of the pain’s severity. This behavior resembles definitions of addictive behavior (Box 31-4). The situation then escalates, either during one admission or more commonly over multiple admissions, and results in a crisis of mistrust between the patient’s feeling neglected and health care professionals’ finding the patient demanding or malingering. The well-described syndrome can complicate issues dramatically and should be recognized early and avoided at best. Treatment should start with acknowledgment of the pain as being real and the need for increased analgesic doses and frequency to the point of regaining the patient’s trust.
Opioids for Acute Pain Management
Acute pain can arise in many clinical situations, including the postoperative period (Chapter 46), trauma, medical illness, childbirth (Chapter 55), and acute exacerbation of chronic and cancer pain (Chapter 72). The most common acute pain syndrome is postoperative pain.
In view of the generally high intensity, rapid onset, and short duration of acute pain, effective medications with a rapid onset of action should be titrated to analgesia quickly. Opioids fulfill these conditions well and are therefore a mainstay of most acute pain treatment. However, mainly because of inappropriate choice of opioids and their dosage, ignorance of pharmacokinetics, and fear of side effects, acute pain remains poorly managed in many settings (Wulf and Neugebauer 1997). Issues specific to opioids in the management of acute pain are discussed in the following sections.
Although non-invasive routes are usually regarded as the ideal choice with an emphasis on oral administration (World Health Organization 1996), this is not always feasible with acute pain inasmuch as the severity of the pain might require a fast onset of analgesia and/or the oral route might be unavailable because of underlying pathology or pre- and postoperative fasting. The intramuscular route has been popular, in particular, in the form of the standard prescription “10 mg IM PRN q4h” (Schug 1999). This approach is possibly one of the major causes of a poor outcome of postoperative pain management because it offers an inappropriate dose via a route of administration that is invasive and not without complications but offers only slow and unpredictable absorption with too long a dosing interval (Austin et al 1980). The ideal parenteral route for acute pain is without doubt the intravenous one, with the subcutaneous route being an alternative. Oral opioids can often be used early in the course of recovery. Epidural administration of opioids, in combination with local anesthetics, is another way to provide excellent postoperative analgesia and improve outcome.
Inappropriate mode of administration is the key reason for the poor outcome of opioid use for acute pain. Myths among health care professionals about side effects and the development of tolerance and addiction influence prescribing (Edwards et al 2001). The use of as-needed prescriptions is in principle appropriate for acute pain treatment because it permits titration of opioid doses against pain relief and adverse effects. However, inappropriately small doses with dosing intervals that are too long are often chosen and then defeat this purpose. Furthermore, the availability of sufficient nursing personnel, attitudes of administering nurses, and patients’ reluctance to bother the nurse are limiting factors of this approach.
Here the development of PCA was the major breakthrough (Owen et al 1988). The idea of permitting the patient to use small incremental doses of opioids at short intervals via a programmable infusion device to find a balance between pain relief and adverse effect was extremely successful. It has since been transferred to many other routes of administration and has proved to be safe and effective (Hudcova et al 2006); in the absence of PCA devices, the “PCA principle” should be applied to prescriptions of opioids for acute pain treatment (Lehmann 1997).
It seems that the choice of opioids for postoperative pain relief relies more on local traditions and personal beliefs than on evidence. In comparative studies it was found that overall, one opioid has no advantages over others and that some patients seem to tolerate one better than another, thus supporting the concept of opioid rotation (Woodhouse et al 1999). Morphine is of potential risk in patients with renal impairment (Glare and Walsh 1991); fentanyl, oxycodone, or hydromorphone is preferable in this setting. Tramadol is a safer alternative in patients at risk for opioid side effects (Macintyre et al 2010).
Initiated by the British hospice initiative and then promoted by the World Health Organization (1986, 1996) internationally, opioids, mainly morphine, were promoted as the mainstay of cancer pain management. The details of this approach are addressed in Chapter 75; issues specific to the use of opioids in this setting are outlined in the following discussion.
Failure of efficacy of a weak opioid should result in the use of a strong opioid (World Health Organization 1996).
Opioid substitution or opioid rotation is the practice of changing from one opioid to another with the aim of improving analgesia and the side effect profile (Mercadante 1999). Differences in individual receptor binding, incomplete cross-tolerance, and differences in the pharmacokinetics and activity of metabolites are some of the possible explanations for the rationale of this concept. There is good evidence that the approach is successful in reducing or limiting adverse effects such as sedation, confusion, and constipation (Vissers et al 2010). As an example, methadone has been used to substitute for morphine and was then found to improve adverse effects in 70% of cancer patients (Bruera et al 1996); similar benefits of such a switch have been shown in patents with chronic non-malignant pain (Fredheim et al 2006).
Although multiple tables giving equianalgesic doses have been published (Table 31-3), they have to be followed with extreme caution. The ratios given are usually mean values with considerable inter- and intra-individual variability and should be seen only as a rough guidance for careful individual titration (Gammaitoni et al 2003). Dose ratios can be dose dependent (Lawlor et al 1998) and may reflect incomplete cross-tolerance and specific effects of specific opioids in specific pain states, such as neuropathic pain.
Table 31-3
OPIOID |
ORAL DOSE EQUIANALGESIC TO ORAL MORPHINE, 10 mg |
| Morphine | 10 mg |
| Codeine | 90 mg |
| Dihydrocodeine | 60 mg |
| Tramadol | 50 mg |
| Pethidine | 100 mg |
| Nalbuphine | 10 mg |
| Oxycodone | 7.5 mg |
| Levorphanol | 2 mg |
| Hydromorphone | 2 mg |
| Butorphanol | 2 mg |
| Oxymorphone | 1.5 mg |
| Methadone | 1 mg |
| Buprenorphine | 0.3 mg |
Data compiled from multiple sources.
Opioid responsiveness is defined as the degree of analgesia achieved while the dose is titrated up to an end point defined by either intolerable side effects or the occurrence of acceptable analgesia (Mercadante and Portenoy 2001). This makes it obvious that opioid insensitivity is rather a relative term than an absolute term. There is a large degree of individual variability in opioid responsiveness, which is influenced by many factors.
The development of intolerable side effects limits dose escalation and thus is an indicator of poor opioid responsiveness. Common adverse effects such as nausea, vomiting, constipation, and pruritus are troublesome to the patient but are rarely dose-limiting factors. However, the greater prevalence of nausea and vomiting in females can cause dose limitations and thereby influence opioid responsiveness (Mercadante and Portenoy 2001). CNS effects such as sedation, delirium, hallucinations, and myoclonic jerks are more often the symptoms that limit dose escalation. This decision also depends on the outcome measurement. If analgesia were the only outcome measure, achieving it with excessive sedation would still be considered opioid responsiveness. However, if analgesia and quality of life are to be considered as a good outcome, sedation would be a dose-limiting factor.
Genetic and environmental variability in opioid receptor expression, variability of other neurotransmitter systems that mediate opioid effects, and variability in the metabolism of opioids may contribute to variability of response (Stamer and Stuber 2007a). Metabolites of morphine have been postulated to affect the analgesic response (Andersen et al 2003).
Even though opioid-insensitive pain cannot be predicted, it can be anticipated in some clinical situations. One is neuropathic pain and another is incident pain (defined as an exacerbation of background pain as a result of an event such as movement). Although the former is no longer regarded as being unresponsive to opioids, both are not completely responsive to these agents. Similarly, patients with high levels of psychological distress and anxiety may not benefit as much from opioid use. Organ dysfunction (renal or hepatic) can further limit dose escalation.
Given the above factors, opioid responsiveness can be addressed by careful clinical assessment, use of co-analgesics, prophylactic treatment of side effects, and judicious titration of opioid doses. Opioid rotation has promising results as discussed earlier (Vissers et al 2010).
Management of cancer pain with opioids has often been linked to hastening of death in these patients. The evidence thus far does not support this notion, and the indication for opioid use in this setting is clearly the provision of analgesia, not affecting survival (Sykes and Thorns 2003). Opioids are used to alleviate pain and enhance comfort and therefore obviously improve quality of life and may possibly enhance survival (Brescia et al Gray 1992).
As outlined in this chapter, opioids have become well established and accepted in the management of acute pain and cancer pain and have good outcomes and minimal risk for tolerance and abuse. These positive experiences have led to the increasing use of opioids in patients with chronic non-cancer pain (CNCP) over the past 15–20 years, in particular, driven by pain clinicians with well-established experience in the area of acute and cancer pain treatment (Portenoy 1996). This new approach was a response to the overwhelming problems caused by CNCP and the inadequacy of current treatment modalities and in stark contrast to previous attitudes of avoidance of opioid exposure in this population. However, simply transferring the concepts and findings of acute and cancer pain management to the treatment of CNCP might be flawed; most of the former is of nociceptive or neuropathic origin, whereas the latter is often the result of central sensitization and multifactorial. These patients have a range of biological, psychological, and social symptoms that are often further complicated by anxiety, depression, and sometimes substance abuse disorders. Therefore they need not simply analgesia, but suffering, dysfunction, psychosocial factors, and dependence on the health care system need to be addressed as well (Stein 1997). It is not surprising that opioids might not achieve the desired outcomes here.
In this context it is of note that well-documented nociceptive (e.g., osteoarthritis [Avouac et al 2007] and neuropathic [Eisenberg et al 2006]) chronic pain states might have a better response to opioids than other chronic pain, although even here good long-term data are missing (Kalso et al 2004).
Most of the current data on the effects of opioids for CNCP are anecdotal, contradictory, and more philosophical and emotional than scientific. The complex manifestation of CNCP, its protracted course and management, and the complexity of outcome measures all contribute to the difficulty of conducting proper randomized controlled trials.
A meta-analysis of the use of opioids for chronic back pain found only limited evidence of some short-term efficacy for this condition (Martell et al 2007). Similarly, a Cochrane Review of long-term opioids for chronic pain showed high rates of discontinuation, only weak evidence of clinically significant pain relief, and inconclusive results on function and quality of life (Noble et al 2010). A different approach to identifying outcomes of opioid treatment of chronic pain was taken in a large epidemiological study from Denmark (Eriksen et al 2006); it reported that, surprisingly, long-term treatment with opioids did not result in any positive outcomes with regard to the treatment goals of pain relief or improvement in quality of life or function.
The above results make obvious the dilemma of managing chronic pain of non-malignant origin—is the goal subjective reduction of pain scores or improvement in physical or psychological function? This debate is ongoing and relates closely to the question of whether opioids are harmful in this setting (Large and Schug 1995). Therefore, the risks associated with opioid use for chronic pain states need to be discussed; these risks lie possibly not just in areas such as the development of tolerance, abuse, and organ toxicity, but there are further physiological and psychobehavioral concerns.
Some experimental evidence indicates that opioids can induce a central nervous state of hyperexcitability (OIH, see earlier), similar to that of patients in chronic pain; the pharmacology of opioid tolerance might be similar to the physiology of chronic pain (Rohde et al 1996).
From a psychological point of view, drug abuse and addiction are relevant risk factors here. As discussed earlier, the prevalence of inappropriate medication use and abuse of prescription medications and other drugs is high in chronic pain patients treated with opioids (Hojsted and Sjogren 2007). Furthermore, patients with chronic pain often have psychosocial and economic risk factors for addictive behavior, and there might be considerable overlap between chronic pain and addictive behavior (Savage 1993).
There are also behavioral concepts of chronic pain management that see opioids in this setting as a risk. When opioid use is made contingent on the expression of pain, opioids can function as reinforcers of pain behavior and drug intake and shift an individual’s sense of control toward the external agent of medication as being the best way to cope with pain (Large and Schug 1995); this is in line with data that patients are more likely to be prescribed opioids when showing greater distress, suffering, and pain behavior (Martell et al 2007). In contrast, patients who take the attitude that they are in control of their own pain do better than those who assume that they have little control and should be helped by some external agent. This notion is formalized in research on “locus of control” and “self-efficacy” (Lipchik et al 1993). The whole concept of behavioral pain management is on gaining control and not on taking away the pain. Thus, reliance on intake of external agents is disturbing because it contravenes this concept of management and has the potential to lock the chronic pain behavior in place indefinitely. This concern is in line with findings that opioid use may lead to a poor functional outcome in patients with chronic back pain (Dersh et al 2008).
Last but not least, diversion of prescription drugs can result in significant risks to society and seems to be becoming an increasing problem in many Western countries in parallel with the more widespread and liberal use of opioids for chronic pain (Davis and Johnson 2008, Fischer et al 2010). Multiple strategies to reduce these risks (Gilson and Kreis 2009), including the development of abuse-deterrent opioid formulations, are discussed (Katz et al 2007).
In conclusion, a recent paper states that "Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions" (Chapman et al 2010). The authors suggest approaches to research that will lead to a better evidence base in the future.
Despite all this controversy, there is wide-ranging agreement on a number of issues (Kalso 2005, Trescot et al 2006, Chou et al 2009):
Most of the current publications and guidelines dealing with the approach agree on a set of principles that should be followed before implementation and during maintenance of opioid therapy in patients with CNCP (Chou et al 2009, Stein et al 2010).
Before commencing opioid therapy in patients with CNCP, it is ideal to establish realistic goals based on the initial assessment. These goals are to be looked at together and are not necessarily achievable as single parameters. Opioids should be regarded not as a treatment modality by itself but as one part of multimodal pain management. In this context, opioids can be used to provide subjective pain reduction, thereby enabling the patient to be better able to cope with other modalities of pain management such as physiotherapy and physical activation. Because of wide interindividual variability in patients’ level of autonomy, it is generally regarded as best practice to consider a trial of opioids and withdraw their use if provision of analgesia has not helped improve function.
Most international and national guidelines have agreed on similar prerequisites for the use of opioids in patients with CNCP (Box 31-5) (Schug and Large 1995, Portenoy 1996, Savage 1999, Chou et al 2009, Stein et al 2010). Some of these prerequisites sound too idealistic to be true. It is hard to imagine how patients with chronic pain who have failed other approaches of pain management and are not coping with their pain are psychologically stable; however, many guidelines make this a prerequisite for opioid therapy. Similarly, excluding patients with a history of substance abuse makes sense theoretically, but it does not take into account the considerable interactions between drug abuse and chronic pain (Savage 2002). Identification of patients at risk might be a more appropriate approach (Passik and Kirsh 2008). Last but not least, to make failure of reasonable attempts to use alternatives such as physical, cognitive–behavioral, and medical approaches a prerequisite leads to opioids being viewed as a last resort, which they are not. This can lead to spending considerable time before initiation of opioids, which leads to loss of patients’ trust and confidence and possibly misses the chance for early rehabilitation under the analgesic cover of opioids.
A therapeutic trial of opioids before a decision in favor of long-term therapy is recommended. Although some centers continue to promote parenteral trials, it seems more clinically useful to initiate a 4-week trial period of the planned therapy with oral opioids and use this period for frequent reviews to achieve dose titration and assessment of clinical efficacy. Ideally, one physician takes the responsibility for initiating and monitoring the trial with prespecified goals and clearly stated end points. Current trends in drug selection are in favor of long-acting μ-receptor agonists such as methadone or slow-release preparations of shorter-acting agents such as morphine, oxycodone, or transdermal fentanyl. Of these, methadone might be a good choice because of its effects on non-opioid receptors (NMDA, noradrenaline, and serotonin), which have beneficial effects in pain modulation. Tramadol has also shown some promising results, possibly for similar reasons, but with a low risk for abuse and diversion (Schnitzer et al 2000). Opioid rotation is useful in the management of CNCP as well (Thomsen et al 1999).
The concept of leaving the final decision to prescribe opioids to a multidisciplinary pain management team or at least more than one physician is good. It avoids coercion of a single practitioner, offers legal protection to some extent, and helps patients in a strained patient–doctor relationship by affording the chance for a “second opinion,” but it is not always an option, depending on access to such teams. Although there is no question that the implementation of long-term therapy requires the patient’s consent, there is extensive debate about the value of a contract or agreement between patient and physician (Arnold et al 2006). Generally, contracts with clear and precise rules are useful as an educational resource for the patient and as a concept of behavioral contracting (Fishman and Kreis 2002).
Once long-term opioid therapy is initiated, patients need to be reviewed frequently, initially at least monthly. At each review, analgesic efficacy, side effects, evidence of aberrant behavior, and improvement in functional status must be assessed. Dose escalation in a reasonable range should not be denied automatically if opioids are well tolerated and there is evidence of improved function and limited adverse effects. Aberrant behavior must be recognized, and features suggestive of such behavior must be reviewed critically. Sometimes patients in whom pain is not adequately addressed or treated to their expectations may have features suggestive of addiction, described as pseudo-addiction (Weissman and Haddox 1989). Treatment in the two situations is entirely different; in patients with features suggestive of improper behavior related to drugs, the appropriateness of opioid use must be reassessed and opioids may need to be withdrawn gradually. With pseudo-addiction, sometimes simple modification of the regimen to cater for incidental pain and breakthrough pain may solve the problem.
After stabilization of therapy and doses, ongoing management and treatment can and should be handed over to the primary care physician of the patient (Fishman et al 2002); review by a pain clinic at longer intervals might continue.
This chapter is based on Chapter 28 of the fifth edition of this textbook, which was co-authored by Neelima Gandham. Her contribution to the current chapter is hereby thankfully acknowledged.
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