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9 Opioids

9 Opioids
The Massachusetts General Hospital Handbook of Pain Management

9
Opioids

Jeffrey Uppington

Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.
—Thomas Sydenham, 1624–1689

I. Terminology
II. Endogenous opioids
III. Classification of opioids
IV. Opioid receptors

1. Mu receptors

2. Kappa receptors

3. Delta receptors

4. Sigma receptors

5. Epsilon receptors

6. Cloned receptors

7. Receptor mechanisms

8. Alternative opioid mechanisms
V. Opioid effects

1. Central nervous system

2. Neuroendocrine effects

3. Gastrointestinal system

4. Cardiovascular system

5. Tolerance, dependence, and addiction

6. Other effects
VI. Precautions
VII. Routes of administration
VIII. Principles of opioid therapy

1.“Mild” versus “strong”

2. The titration principle

3. Choice of opioid

4. Short-acting versus long-acting

5. Prescribing opioids

6. Controlling side effects

7. Treating overdose
IX. Specific opioids
X. Conclusion
Selected Reading

Opioids are the core pharmacologic treatment for pain. They are the mainstay for the treatment of both acute and cancer pain, and although controversy still exists over their use in chronic nonmalignant pain, they are increasingly used for this indication also. They are the only pain medications that have no ceiling effect, and are therefore the only systemic treatment for severe accelerating pain. Any person treating pain should understand the effects and proper usage of these important drugs.
I. TERMINOLOGY
Opiates are drugs derived from opium, which is obtained from the juice of the poppy Papaver somniferum. They include morphine, codeine, and various semisynthetic congeners derived from them and another component of opium, thebaine. The term opioid applies to substances with morphine-like activity, including agonists and antagonists as well as naturally occurring and synthetic opioid peptides. Endorphin is a generic term applying to the endogenous opioid peptides. There are three families of endogenous opioids—the endorphins, the enkephalins, and the dynorphins. The word narcotic, derived from the Greek word for stupor, originally referred to any drug that induced sleep, but it later became associated with the strong opiate analgesics. The term is no longer useful pharmacologically as it is being increasingly used in the legal and regulatory context to refer to a wide variety of abused substances.
II. ENDOGENOUS OPIOIDS
Each of the three families of opioid neuropeptides (endorphins, enkephalins, and dynorphins) is derived from a distinct precursor polypeptide and has a distinct anatomic distribution. Like peptide hormones, endogenous opioids have biologically inactive precursors that generate active agents only after enzymatic cleavage. The precursor for beta-endorphin, pro-opiomelanocortin, also contains peptide sequences for adrenocorticotropin (ACTH) and melanocyte-stimulating hormone (MSH), illustrating the close relationship between endogenous opioids and hormone systems.
III. CLASSIFICATION OF OPIOIDS
Opioids can be classified as naturally occurring, semisynthetic, and synthetic (Table 1). Morphine, codeine, papaverine, and thebaine are naturally occurring. The semisynthetic drugs are derived from morphine, codeine, and thebaine. The synthetic drugs structurally resemble morphine but do not occur in nature. They are produced by gradually reducing the number of rings from the fivering structure of morphine, through the four-ring morphinans and the three-ring benzomorphinans, to the two-ring phenylpiperidines (Fig. 1).

Table 1. Classification of opioids

Figure 1. Structure of morphine-like opioids. A: Morphine. B: Morphinan. C: Benzomorphan. D: Phenylpiperidine. E: Tyramine moiety of endogenous opioids. Note the progressive removal of ring structures from five-ring morphine to two-ring phenylpiperidine. (Reproduced with permission from Carr DB. Opioids. Int Anesthesiol Clin 1988;26:273.)

There are alternative classifications of opioids. The drugs may be grouped according to the specific receptors they act on (see later). Another useful distinction is whether they are agonists, antagonists, or some combination of the two (Table 2).

Table 2. Alternative classification of opioids

IV. OPIOID RECEPTORS
Opioids act via specific receptors on cell membranes. Specific opioid receptors have been proposed on the basis of a mixture of clinical and laboratory observations. The structure of opioid receptors is currently understood at cellular, molecular, and genetic levels, although the existence of some receptor types proposed on clinical grounds has not yet been confirmed in the laboratory. There are five proposed classes of opioid receptor: mu, delta, kappa, sigma, and epsilon.
1. Mu receptors
It seems likely that morphine and morphine-like drugs produce analgesia primarily through interaction with mu receptors. These receptors are present in large quantities in the periaqueductal gray matter (brain) and the substantia gelatinosa (spinal cord). Activation of mu receptors results in analgesia, euphoria, respiratory depression, nausea and vomiting, decreased gastrointestinal (GI) motility, tolerance, and dependence. Using selective antagonists, two distinct subgroups of the mu receptor have been identified: mu1, found supraspinally, and mu2, found in the spine. Both respiratory depression and constipation (reduced GI motility) are thought to be mediated through mu2 receptors. The concept of a selective mu1 agonist, which could theoretically produce analgesia without respiratory depression, is intriguing but unrealized. Beta-endorphin has a high affinity for mu receptors, as do the enkephalins. Dynorphin also binds to the mu receptor, but not as avidly as it does to the kappa1 receptor.
2. Kappa receptors
Activation of these receptors also causes analgesia, but it causes less respiratory depression than activation of mu receptors. Kappa receptor activation produces dysphoria and hallucinations rather than euphoria. Several kappa-receptor subtypes have been proposed on the basis of binding studies, but their actions have not been fully elucidated. Dynorphin A is the endogenous ligand for the kappa1 receptor.
3. Delta receptors
Using selective agonists and antagonists, studies have established delta-receptor analgesia both spinally and supraspinally, although the spinal system appears more robust. Delta1- and delta2-receptors have been proposed on the basis of differential sensitivity to several antagonists. The enkephalins are the endogenous ligands for the delta-receptors.
4. Sigma receptors
The sigma receptor may not be a true opioid receptor, as its actions are not antagonized by naloxone. There is some evidence that it may be the receptor for phencyclidine (“angel dust”). Although the psychotomimetic effects of drugs such as pentazocine were initially attributed to sigma receptors, the status of these sites is presently uncertain.
5. Epsilon receptor
This has been postulated as the specific receptor for betaendorphin, although beta-endorphin is known to act at both mu and delta receptors.
6. Cloned receptors
The mu, delta, and kappa receptors have been cloned and their genes identified. They are the only opioid receptors that have been cloned, despite an intensive search for genes corresponding to opioid-receptor subtypes. The cloned opioid receptors have characteristics of typical G-protein-coupled receptors. There are seven hydrophobic regions that span the cell membrane, with three extracellular and three intracellular loops. There are an intracellular carboxy-terminal tail and an extracellular amino-terminal tail. The amino acid sequences of the different opioid receptors are approximately 65% identical to each other. The regions of highest similarity are the sequences predicted to lie in the seven transmembrane-spanning regions and intracellular loops. The extracellular regions that differ in amino acid sequence may contain the unique ligand-binding domains for each receptor (Fig. 2).

Figure 2. Amino acid sequence identity among the three cloned opioid receptors. Comparison of the amino acid sequences of the cloned mouse d and k receptors and the rat p receptor reveals that approximately 65% of the residues are either identical or similar. Amino acid residues that are identical or similar among the receptors are in black, and those that are not similar are in open circles. Note that the intracellular loops and transmembrane-spanning regions I, II, III, V, and VII are very similar in amino acid sequence. In contrast, the amino and carboxy termini are very different, as are extracellular loops two and three and transmembrane-spanning region IV. From Goodman and Gilman. The Pharmacological Basis of Therapeutics, 9th ed. 1996.

7. Receptor mechanisms
Opioid receptors are coupled to G proteins and are thus able to affect protein phosphorylation via second messenger systems, thereby altering ion channel conductance. Opioids act both preand postsynaptically. Presynaptically, they inhibit the release of neurotransmitters, including substance P and glutamate. Postsynaptically, they can inhibit neurons by opening potassium channels that hyperpolarize the cell. There is evidence that opioids produce both short- and long-term effects on neural function, and they may play a distinct role during early embryonic development.
Administration of opioids significantly reduces the facilitation of nociceptive processing (e.g., “windup”). Opioids (including endogenous opioids) can also affect opioid gene regulation, with possible short- and long-term effects and local as well as distal effects.
8. Alternative opioid mechanisms
Not all nociceptive mechanisms are mediated by opiate receptors. It is known that N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors are involved in nociceptive transmission in the spinal dorsal horn. Norepinephrine, serotonin, and sodium channels are also involved, and it is possible that a central nitric oxide–cyclic guanosine monophosphate signaling pathway may help mediate nociception.
It appears that some opioid actions are not mediated by opioid receptors. This observation is potentially important for understanding pain and analgesic mechanisms. Thus, methadone, meperidine, and tramadol inhibit serotonin and norepinephrine reuptake. Methadone, meperidine, and other opioids are antagonists of the NMDA amino acid excitatory pathway. Meperidine blocks sodium channels and has local anesthetic properties.
V. OPIOID EFFECTS
1. Central nervous system
(i) Analgesia, mood, and consciousness
Opioids selectively relieve pain without affecting other sensory modalities. Pain can be described as a specific sensation (burning, shooting, throbbing), or in terms of suffering (excruciating, miserable). Opioids alter the sensation of pain as well as the affective response. Patients often say that their pain is still present but that they feel more comfortable. Occasionally, patients experience euphoria or dysphoria, more so when these drugs are used for recreational purposes. Useful analgesia occurs without loss of consciousness, although high doses of opioids do produce unconsciousness, and drowsiness is a common side effect.
(ii) Respiratory depression
Opioids of the morphine type depress respiration by acting directly on the respiratory centers in the brainstem. Equianalgesic doses of morphine-like opioids have the same degree of respiratory depression as morphine itself. The effect is chiefly via mu receptors (probably the mu2 subpopulation). Partial agonists and agonist–antagonist opioids are less likely to cause severe respiratory depression, as are the selective kappa agonists.
Therapeutic doses of morphine depress all phases of respiration, respiratory rate, and minute volume. At the same time, the responsiveness to carbon dioxide (CO2) is decreased and thus the CO2 response curve is shifted upward and to the right. The degree of respiratory depression is dependent on opioid dose and other factors, and apnea is a true risk. Pain and stimulation counteract respiratory depression, whereas sedative drugs such as the benzodiazepines potentiate the respiratory depression. Natural sleep also reduces CO2 responsiveness and is additive to the opioid effect. Unexpected respiratory depression may occur in relation to variations in serum concentration, concomitant drug use, and varying degrees of pain and stimulation. Naloxone effectively reverses the respiratory depression.
(iii) Nausea and vomiting
Nausea and vomiting from opioids is the result of the direct stimulation of the chemoreceptor trigger zone (CRTZ). The CRTZ is situated in the area postrema in the floor of the fourth medulla. There is also an associated increase in vestibular sensitivity, so that opioid-induced nausea tends to be exacerbated by movement. Treatment includes opioid dosage reduction, antidopaminergics [e.g., droperidol, prochlorperazine edisylate (Compazine), metoclopramide], anticholinergics (e.g., scopolamine), or serotonin antagonists (e.g., ondansetron).
(iv) Cough
Opioids depress the cough center in the medulla. There is no obligatory relationship between cough suppression and respiratory depression, and effective antitussive agents are available that do not depress respiration in clinical doses, such as dextromethorphan. The antitussive receptors are less sensitive to naloxone than receptors involved in analgesia.
(v) Miosis
Mu and kappa agonists constrict the pupil by an excitation of the Edinger-Westphal nucleus (parasympathetic) of the oculomotor nerve. Tolerance to the miotic effects occurs with long-term opioid use, but addicts with high circulating blood concentrations exhibit small pupils. The pupillary effects of opioids are altered by concomitant use of other drugs including general anesthetics. Morphine reduces intraocular pressure.
(vi) Convulsions
In animals, high doses of morphine and related opioids cause convulsions. The drugs stimulate hippocampal pyramidal cells, probably by inhibiting release of gamma-aminobutyric acid (GABA) at the synaptic level. Selective delta-agonists may do the same. In humans, convulsions are rarely seen because seizure-producing doses are extremely high and not administered. However, meperidine is particularly prone to produce seizure activity through its metabolite normeperidine, accumulation of which is most likely to occur in patients with renal dysfunction and in the elderly. Meperidine-induced seizures are relatively common, and for that reason the use of meperidine is discouraged, particularly in susceptible patients, for chronic pain. Naloxone can be used to treat seizures, but it is more effective at treating convulsions caused by morphine and related drugs than by meperidine.
(vii) Hypothalamic effects
Opioids can cause decreases in body temperature. The chief mechanism is alteration of the equilibrium point of the hypothalamic heat-regulating mechanism, although opioid-induced vasodilation may worsen the effect. Although shivering is not observed consistently after opioid anesthesia, it does occur frequently after inhalation anesthesia. Small doses of opioid (particularly meperidine) can attenuate or abolish the shivering through a mechanism that is poorly understood.
2. Neuroendocrine effects
Opioids have a number of neuroendocrine effects. High-dose opioid therapy reduces stress hormone release (glucocorticoids and catecholamines). It is not at all clear to what extent and under what conditions this is a desirable effect. Evidence is emerging that high-dose opioids may also suppress immune responses, which clearly is not a desirable effect. Opioids suppress hypothalamic releasing factors, thus suppressing the release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropin (ACTH), and beta-endorphin. Cortisol and testosterone levels are thereby reduced. In women, the menstrual cycle may be disrupted, and testosterone levels may be reduced in men. Some opioids also reduce growth hormone production. During chronic opioid administration, tolerance to these effects develops. Thus heroin addicts maintained on methadone normalize their disrupted menstrual cycles (women), and plasma concentrations of LH and testosterone (men) return to normal.
3. Gastrointestinal system
Stomach
Gastric motility is decreased, prolonging gastric emptying and increasing the risk of esophageal reflux. The passage of gastric contents through the duodenum is usually delayed. Mu agonists usually decrease gastric acid secretion, but stimulation can occur. Indirect effects, such as increased secretion of pancreatic somatostatin, predominate.
Small intestine
Biliary, pancreatic, and intestinal secretions are diminished, and the digestion of food is delayed. The duodenum is affected more than the ilium. Water is absorbed more completely and the viscosity of bowel contents increase.
Large intestine
Peristaltic propulsive waves are decreased or abolished in the colon. Bowel tone increases. Water is absorbed, which desiccates the feces and slows their passage. In postoperative patients, prolonged ileus is a problem. In patients taking chronic opioids, constipation is common and these patients should take stimulant laxatives.
Biliary tract
The sphincter of Oddi constricts, and bile duct pressure may increase. Despite this, little clinical effect is seen. Naloxone reverses the effects, as does glucagon. Atropine and nitroglycerine only partially reverse the effects. Morphine and morphine-like drugs are thought to have a worse effect than meperidine and its derivatives, but the validity of this finding is in doubt.
4. Cardiovascular system
Opioids exhibit a number of actions on the cardiovascular system. Histamine release and peripheral vasodilation accompany morphine use and that of some other opioids. High doses of any opioid will reduce sympathetic output and thus allow a greater preponderance of parasympathetic effects. The pulse rate may be slowed by stimulation of the vagal center, especially with high doses. There is little direct effect on the myocardium, but the peripheral effects may reduce myocardial oxygen consumption, left ventricular end diastolic pressure, and cardiac work. High doses, low blood volume, and combination with other drugs such as phenothiazines accentuate the hypotensive effects.
5. Tolerance, dependence, and addiction
These phenomena are discussed in detail in Chapter 30 and Chapter 35, but as it is important to understand these phenomena when prescribing opioids, a brief overview is included here. Whereas tolerance and dependence are likely (almost inevitable) consequences of chronic opioid use, addiction is a behavioral problem that arises only in certain individuals. Tolerance is the need for increasing doses to achieve the same analgesic effect, and it is a form of tachyphylaxis. Tolerance to side effects also occurs. Changing from one opioid to another is often effective in reducing tolerance because of incomplete cross-tolerance between opioids (see Chapter 32).
Dependence, or physical dependence, arises when continuous exposure to a drug is necessary to avoid withdrawal symptoms. Slow weaning of opiate drugs usually prevents a withdrawal syndrome from appearing.
Addiction implies socially destructive drug-seeking behavior, and it arises in certain individuals who are predisposed to it. Addiction rarely occurs in patients treated with opioids for acute or cancer pain, but the risk of addiction should always be considered when prescribing opioids for chronic nonmalignant pain (see Chapter 30).
In the treatment of acute and cancer pain, it is often necessary to reassure patients that the risk of their developing addiction is extremely low, and that tolerance and dependence are not addiction.
6. Other effects
(i) Chest wall rigidity
Rapid infusion of a large bolus injection of potent opioids can induce increased muscle tone, mainly of the chest wall and abdomen. The opioids most associated with this phenomenon are fentanyl, sufentanil, and alfentanil. The mechanism of the muscle rigidity is not clear, but it is resolved with muscle relaxants or opioid antagonists.
(ii) Ureter and bladder
The ureteral tone and amplitude of contraction may increase with therapeutic doses of opioids. The urinary voiding reflex is inhibited, and external sphincter tone and bladder volume increase. Urinary retention may result. Tolerance to these effects usually occurs over time.
(iii) Skin
Therapeutic doses of morphine can produce dilation of the cutaneous blood vessels. Histamine release is the likely cause. Histamine release also probably accounts for the local urticaria sometimes seen after injection. Pruritus may occur, particularly after neuraxial administration of opioids. Naloxone does not abolish the histamine effects, but it does reverse itching. Antihistamines are also effective for opioid-induced itching, even if the presumed mechanism of effect is central (as in neuraxial administration).
VI. PRECAUTIONS
Hepatic and renal diseases
In hepatic and renal disease processes, because of decreased metabolism and elimination of opioids, some concerns arise:

Active metabolites of morphine and codeine, especially morphine-6-glucuronide, may accumulate.

Meperidine administration can lead to accumulation of normeperidine, causing CNS excitation with tremors or seizures.

Repeated doses of propoxyphene may cause naloxone insensitive cardiac toxicity secondary to its metabolite norpropoxyphene.
Respiratory disease
Caution is advisable when using opioids whenever respiratory reserve is diminished (e.g., emphysema, kyphoscoliosis, severe obesity). Opioids that release histamine may precipitate bronchospasm, especially in asthmatics. Depression of the cough reflex may be deleterious in patients with copious secretions (e.g., those with pneumonia, bronchiectasis, prior thoracotomy).
Head injury
An increase in PCO2 from respiratory depression can lead to elevated intracerebral pressure. Meiosis, vomiting, and mental clouding, which are important clinical signs in the evaluation of head injury, may be obscured.
Allergic reactions
True allergies to opioid medications are rare but do occur. More commonly, patients mistakenly believe they are allergic because they have suffered a side effect. Wheals at the injection site are from histamine release.
Drug interactions
Opioid effects may be potentiated by concomitant drug use, and these effects are not unusual. In particular, the sedative and respiratory depressant effects of opioids may be exaggerated by con-comitant administration of drugs with sedative properties (e.g., antihistamines, anxiolytics, antiemetics). On the other hand, opioid sedative and respiratory depressant effects may be offset by stimulants (e.g., amphetamines, analeptics). The only specific dangerous interaction is that between meperidine and the monoamine oxidase inhibitors (MAOIs). This results in a potentially fatal excitatory reaction with delirium, hyperpyrexia, and convulsions, and it is caused by central serotonergic overactivity secondary to blockage of neuronal uptake of serotonin by meperidine.
VII. ROUTES OF ADMINISTRATION
Opioids may be administered by a number of routes, although the oral route is the route of choice in most situations. Some relatively new routes have been described.
Oral
There is usually a significant first-pass effect, so that the oral dose of opioids needs to be higher than the parenteral dose (commonly 3:1). For example, the bioavailability of oral morphine is only about 25%. The duration of oral opioids is prolonged by their slow absorption through the GI tract. Sustained-release forms are available that further prolong the action. The oral route is simple because of its accessibility, and it is relatively safe because of the slow absorption of the drug. Opioids are also relatively easy to titrate using this route.
Parenteral
The clinical parenteral routes of administration are the intravenous, intramuscular, and subcutaneous routes. Patientcontrolled analgesia (PCA) may be used for all these routes, although the intravenous route is most common. PCA via the subcutaneous route is chosen for home care.
Transdermal
Passive diffusion of certain drugs through the skin is possible. A drug is delivered via patches that contain a drug reservoir and a controlling membrane. Fentanyl has been used in this way for several years, and patches are available that deliver doses from 25 to 100 µg/hr. After the initial placement of the patch, it may take 12 hours for the maximal blood level to be reached, after which analgesia persists for up to 72 hours (although less in some patients). Patches are changed every 2 to 3 days. The liver is bypassed, blood levels are fairly constant, and the system is convenient and comfortable. The great disadvantage of the transdermal route is that rapid titration is impossible (either up or down). However, for patients with stable pain, especially patients who cannot take oral medications, the patches are useful. This is also a useful way to give fentanyl, which is a highly specific mu receptor agonist thought to be particularly effective for neuropathic pain.
Neuraxial
The epidural, intrathecal, and intraventricular routes of administration allow smaller doses, prolonged duration of action, and minimal systemic side effects. The aim of this form of administration is to produce a specific spinal effect called selective spinal analgesia. Delayed respiratory depression may occur with larger doses, particularly with morphine, which is extremely nonlipophilic and therefore subject to rostral flow in the watery cerebro spinal fluid where this drug tends to accumulate. This occurs when the drug reaches the respiratory center in the brainstem.The more lipophilic opioids tend to diffuse across lipid bilayers more readily, and they generally do not travel rostrally (see Chapter 21). Neuraxial opioids are used commonly to treat postoperative pain and less commonly to treat cancer pain.
Rectal
Morphine may be given rectally and suppositories are available. Plasma morphine concentration after oral and rectal routes suggests that the oral-to-rectal potency ratio for morphine is 1:1. Thus, oral and rectal doses are the same. Slow-release morphine tablets have been given rectally when patients are no longer able to swallow tablets.
Transmucosal
The more lipophilic opioids are readily absorbed through buccal, nasal, or gingival mucosa. First-pass effects in the liver are avoided and rapid onset of action is possible. Buprenorphine, butorphanol, fentanyl (fentanyl lollipop), and sufentanil have all been given via this route.
VIII. PRINCIPLES OF OPIOID THERAPY
1.“Mild” versus “strong”
There is really no such thing as a mild opioid, since all opioids can be titrated to achieve equianalgesic effects and there is no ceiling effect to any opioid. However, certain opioids have traditionally been considered mild either because dosing is limited by side effects (e.g., codeine’s constipating effect), or more often because they have been offered by the pharmaceutical companies in combined preparations in which the secondary drug (e.g., acetaminophen or aspirin) limits dosing (e.g., Percocet, Percodan, Vicodin, Tylenol #3). These combination therapies are useful for short-term management of mild to moderate pain such as acute pain after surgery or trauma, but they are less useful in long-term pain management because of their dose limitations.
In fact, physicians are moving away from the World Health Organization (WHO) concept of using these drugs as second-level therapy in the treatment of cancer pain (see Chapter 32) because of the inability to titrate them. Most authorities now encourage the earlier adoption of small doses of “strong” opioids (i.e., any single opioid) in preference to combination therapies for the treatment of chronic and cancer pain. Clearly, adjuncts can be given at the same time, but giving these as a separate preparation allows the opioid to be titrated to need.
2. The titration principle
For many reasons, not the least of which is to avoid side effects, particularly respiratory depression, the best principle for giving opioids is to start low (standard starting doses of opioids for acute pain are presented in tables in Chapter 21, and for chronic pain in Appendix VI) and titrate up (or down) in increments until optimal (i.e., maximal analgesia with acceptable side effects). The size of the starting dose and the size and timing of incremental increases clearly depend on the patient’s opioid sensitivity, which will depend in turn on the patient’s medical condition and whether tolerance has developed.
The only exception to this principle is when PCA or intravenous infusions are used to treat acute severe pain. In these cases, it is safer to give a monitored bolus to achieve comfort, then maintain comfort using standard or near-standard PCA or infusion doses. This is safer than rapidly increasing PCA or infusion doses in an effort to achieve pain relief in patients who not only are opioid naive but also have probably been given multiple centrally acting depressant drugs in the course of treatment. Once these patients become comfortable and can sleep, overdose may occur if a highdose infusion or frequent large bolus dosing is allowed to continue.
3. Choice of opioid
Combination mild opioids such as Percocet, Vicodin, and Tylenol #3 are acceptable choices for mild to moderate short-term pain, especially considering physicians’ familiarity with their use. Demerol is often avoided, especially for long-term use, because of the possibility of normeperidine toxicity and because its euphoric effects result in its being often favored by addicts. Likewise, propoxyphene (Darvon, Darvocet) is avoided because of the possibility of norpropoxyphene toxicity (see the section “Precautions”) and because its analgesic effect at standard doses is weak. Long-term morphine use should be avoided in patients with renal dysfunction, including the elderly (>80 years) because of the likelihood of morphine-6-glucuronide accumulation.
Partial agonists (e.g., buprenorphine) and mixed agonist/antagonists (e.g., pentazocine, nalorphine) are sometimes chosen because of their low potential for abuse and respiratory depression. However, pure agonists are preferred, particularly in chronic pain patients, because of their superior efficacy and because they are more easily titrated. Also, difficulties arise in switching opioids when mixed agonists/antagonists are used and the effects of one drug (e.g., an analgesia) are reversed by another.
Otherwise, any opioid is suitable, and preference is often dictated by physician familiarity and by patient choice. It is worth asking patients if they have received opioids in the past and have a preference, because efficacy and side effects are often patient dependent and idiosyncratic.
4. Short-acting versus long-acting
Several choices of long-acting opioids are now available (MS Contin, OxyContin, Duragesic, methadone) making the use of longacting opioids highly feasible. In the treatment of chronic pain, it is preferable to base therapy on a long-acting preparations and to use short-acting drugs for “breakthrough” pain (i.e., pain that breaks through the analgesia achieved by a long-acting medication and does so because of factors such as activity, anxiety, or time of day). In fact, in the treatment of chronic nonmalignant pain (CNMP), it is often preferable to avoid short-acting medication altogether. Long-acting opioid therapy is associated with less euphoria and dysphoria (and therefore has less addictive potential), which is another reason for preferring it in chronic pain states. As a general principle in chronic pain management, long-acting therapy is maximized and short-acting pain is minimized. In CNMP, short-acting opioids are avoided so the patients can learn to use other means to control their breakthrough pain. Long-acting preparations may also be useful in the treatment of resolving acute pain, when analgesic needs are predictable and the patient would prefer twice daily to more frequent dosing.
5. Prescribing opioids
In the hospital setting, prescribing opioids is relatively easy and regulatory restrictions apply particularly to the pharmacy and to those actually administering the drugs (nurses and anesthesiologists). Hospital personnel are generally comfortable with using opioids within regulatory guidelines and restrictions. Prescribing opioids for home use is much more difficult. Each state has its own regulations and the prescribing physician must be familiar with these. The federal U.S. Drug Enforcement Administration guidelines for the prescription of controlled substances are presented in Appendix VI. The U.S. Food and Drug Administration drug schedules are presented in Appendix VII. The Massachusetts General Hospital (MGH) guidelines for prescribing opioids for CNMP are presented in Appendix V.
6. Controlling side effects
Respiratory depression is rightly the most feared of the opioid side effects. Hypoxia, apnea, and even death can occur with opioid use. However, this is much more likely to occur when opioids are used for acute rather than chronic pain. Obeying the principles of acute pain management (Section V) and the opioid titration principle (discussed earlier) will avoid respiratory depression in most cases. Nausea and vomiting are also far less likely to be troublesome when opioids are used for chronic rather than acute pain.
When side effects do occur, they can be treated either by reducing opioid dose, by switching opioid, or by giving an antiemetic. Constipation is a common complication of chronic opioid treatment, so preventive treatment should always be offered in conjunction with chronic opioid therapy. This should be with stimulant laxatives (e.g., Senokot, Lactulose), not with bulk-forming laxatives, which do not solve the problem of slow transit time and may actually worsen the situation. Other side effects are uncommon and should be treated by dose reduction or symptomatically if necessary.
7. Treating overdose
Overdose may result from clinical overdose, accidental overdose in addicts, or a suicide attempt. Death is nearly always attributable to respiratory failure, but if this is being treated with ventilation, very high doses of opioid are safely tolerated. Blood pressure may fall progressively, the patient is flaccid and cannot be roused. Noncardiogenic pulmonary edema is possible and frank convulsions may occur with very large doses. The pupils are pinpoint, unless hypoxia intervenes, and then they may dilate.
Treatment is supportive, with ventilation and careful fluid management. Naloxone may be given to reverse the respiratory depression, but large doses given quickly can precipitate withdrawal or rebound increases in sympathetic nervous system activity. The safest approach is to dilute the standard 0.4 mg naloxone with 10 mL of fluid and titrate carefully to effect. It should be remembered that naloxone has a short duration (a shorter half-life than most agonists) and re-narcotization can occur. Repeat doses of naloxone or an infusion may be needed.
IX. SPECIFIC OPIOIDS
The structures of some commonly used opioid agonists, partial agonists, and antagonists are shown in Figure 3. Opioid conversion doses are shown in Appendix VIII.

Figure 3. Structures of opioid agonists, partial antagonists, and antagonists.

Morphine
Morphine remains the standard with which all other opioids are compared. It is widely used, and it is recommended as a standard by the WHO because of its wide availability and low cost. One third of morphine is bound to plasma protein and the unbound fraction is ionized at physiologic pH; thus the drug is very hydrophilic. Therefore, although it is distributed widely in the body, it has limited ability to penetrate tissues. It is for this reason that morphine given epidurally or intraspinally can spread rostrally in cerebrospinal fluid and cause delayed respiratory depression.
Morphine is metabolized by the liver. The major metabolites are morphine-3-glucuronide and morphine-6-glucuronide. Whereas morphine-3-glucuronide is inactive, morphine-6-glucuronide is more potent than morphine itself and has a longer half-life. The glucuronides are excreted by the kidneys and patients with renal dysfunction can accumulate morphine-6-glucuronide and develop prolonged opioid effects, including respiratory depression. On the other hand, patients in liver failure tolerate morphine up to the point of hepatic pre-coma because glucuronidation is rarely impaired. Intravenous (IV) injection of morphine results in rapid peak plasma levels, but peak effector site (brain and spinal cord receptors) concentrations occur 15 to 30 minutes later, so there is a relatively slow onset of peak central nervous system (CNS) effects. Plasma half-life after an IV bolus is 2 to 3 hours. The initial dose given intramuscularly (IM) or subcutaneously (SC) is highly variable, although 10 mg for a 70-kg healthy patient is reasonable. The high first-pass effect means that the oral dose is approximately three times that of the parenteral dose or more. Preservative-free morphine (Duramorph) given in small doses epidurally (1 to 4 mg) or intrathecally (0.1 to 0.4 mg) can produce profound analgesia of long duration (up to 12 to 24 hours). These are conservative doses given at MGH for patients who are in unmonitored beds. Higher doses (up to 10 mg epidurally or 1 mg intrathecally) can be given to monitored patients in intensive care or step-down units.
Preparations

Morphine sulfate injections, 1, 5, 8, 10, 15, and 30 mg/mL; oral tablets, 8, 10, 15, and 30 mg; rectal suppositories, 5, 10, 20, and 30 mg.

Morphine sulfate controlled release (MS Contin) tablets, 15, 30, 60, and 100 mg; Oramorph SR tablets, 30, 60, and 100 mg.

Morphine sulfate immediate release (MDIR, Roxanol, Rescudose, MS/L) oral solution, 2 and 4 mg/mL; oral concentrate, 20 mg/mL; tablets and capsules, 15 and 30 mg.

Morphine sulfate preservative-free solution (Duramorph and Astramorph) for intravenous, epidural, or intrathecal use, 0.5 and 1.0 mg/mL.

Morphine sulfate preservative free (Infumorph) for continuous microinfusions for implantable epidural or intrathecal pumps, 10 and 25 mg/mL.
Formulations containing morphine for the treatment of diarrhea include paregoric and laudanum.
Codeine
Codeine is less potent than morphine but it has a high oral-toparenteral potency ratio. Codeine is largely metabolized by the liver, and the byproducts are excreted by the kidney. About 10% of codeine is demethylated to morphine. Its analgesic action is probably related to this conversion. It has a significant antitussive action, probably involving receptors that bind codeine itself. The plasma half-life is 2 to 4 hours. Codeine is available in combination with acetaminophen or aspirin.
Preparations

Codeine phosphate injections, 15, 30, and 60 mg/mL; tablets, 15, 30, and 60 mg; oral solution, 3 mg/mL.

Codeine sulfate tablets, 15, 30, and 60 mg.
Hydrocodone
Hydrocodone is a semisynthetic codeine derivative with analgesic and antitussive properties, used most commonly in combination with acetaminophen in Vicodin.
Preparation

Hydrocodone bitartrate (Vicodin) tablet, 7.5 mg with acetaminophen 750 mg.
Heroin
Heroin, or diacetylmorphine, is an atypical pro-drug. It has no direct action itself on the opioid receptor, but is rapidly metabolized to 6-monoacetylmorphine and subsequently to morphine. It is not available for clinical use in the United States, but is available in Canada and the United Kingdom. Although many have touted heroin as having advantages over morphine, all present evidence suggests that this is not so. It does come in a preservative free powder and it has a high solubility, so high concentrations can be made, but other potent soluble drugs such as hydromorphone can be substituted.
Hydromorphone
This semisynthetic derivative of morphine is 10 times more potent than its parent compound. After parenteral injection, levels rise rapidly but there is a slower onset of CNS effects. Plasma half life is 2 to 3 hours after an IV dose. IM injection delays peak plasma levels and CNS effects. Oral dosing takes 45 minutes or so for peak effects. Typical doses are 2 to 6 mg orally and 1.5 mg parenterally every 3 to 4 hours.
Preparations

Hydromorphone hydrochloride (Dilaudid) injections, 1, 2, and 4 mg/mL; tablets, 1, 2, 3, 4, and 8 mg; suppository, 3 mg; cough syrup, 1 mg in 5 mL; oral liquid, 1 mg/mL.

Hydromorphone hydrochloride (Dilaudid HP) highly concentrated for opioid-tolerant patients, 10 mg/mL.
Oxycodone
Oxycodone is a synthetic thebaine derivative with a profile and potency similar to that of morphine. It has typically been used in combination with nonopioids (Percocet, Percodan), but more recently it has been formulated as a long-acting preparation (OxyContin), which has popularized its use in cancer and other pain states. Immediate-release oxycodone has also become more popular, partly because it makes sense to prescribe it for breakthrough pain in patients taking OxyContin and partly because it is now perceived as a strong, titratable opioid rather than as a weak, nontitratable opioid (in combination therapies). OxyContin and oxycodone are a useful substitute for MS Contin and immediaterelease morphine, particularly in the elderly who are sensitive to morphine-induced sedation and mental status change and to morphine-6-glucuronide accumulation.
Preparations

Oxycodone hydrochloride immediate release (OxyIR) capsule, 5 mg; (OxyFAST) concentrated oral liquid, 20 mg/mL.

Oxycodone hydrochloride controlled release (Oxycontin) tablets, 10, 20, 40, and 80 mg.

Oxycodone hydrochloride (Percocet) tablet, 5mg with 325 mg acetaminophen; (Tylox) capsule 5 mg with 500 mg acetaminophen.

Oxycodone hydrochloride (Roxicet) oral solution, 5 mg with 325 acetaminophen per 5 mL.

Oxycodone hydrochloride (Percodan) tablet, 5 mg with 325 mg aspirin.

Oxycodone hydrochloride (Roxicodone) tablet, 5 mg; oral solution, 5 mg in 5 mL; (Intensol) concentrated oral solution, 20 mg/mL.
Meperidine
Meperidine is 70% protein bound, which is more highly protein bound than morphine. Parenteral and oral doses are similar. The analgesic effects of meperidine are detectable approximately 15 minutes after an oral dose, reach their peak effect in 1 to 2 hours, and then gradually subside over several hours. Onset after parenteral administration of the same dose is within 10 minutes, and the peak is in 1 hour. Clinical duration of effective analgesia is between 2 to 4 hours. The usual initial dose is between 50 and 100 mg. The drug has vagolytic activities, and it is the only opioid that may produce tachycardia. Meperidine is eventually metabolized to normeperidine.
This metabolite has a half-life of 15 to 20 hours and is eliminated by both the kidney and the liver. Decreased renal or hepatic function can cause normeperidine to accumulate. The half-life is extended in the elderly. Thus in some individuals, there can be metabolite buildup. Normeperidine is toxic and large doses can cause tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions. If meperidine is combined with monoamine oxidase inhibitors (MAOIs), a number of reactions may be seen, including severe respiratory depression or excitation, delusions, hyperpyrexia, and convulsions. Meperidine has weak local anesthetic activities. This drug is generally avoided except for short-term use because of the risk of normeperidine toxicity and because of its high abuse potential.
Preparations

Meperidine hydrochloride (Demerol) injection, 25, 50, 75, and 100 mg/mL; tablets, 50 and 100 mg; syrup, 50 mg in 5 mL; (Mepergan) injection, 25 mg/mL with 25 mg promethazine.
Cogeners of meperidine are diphenoxylate hydrochloride (Lomotil) and loperamide hydrochloride (Imodium), which are used to treat diarrhea.
Levorphanol
This drug is a morpinium, and it is the only example in this series that is commercially available. It has a long duration of action and pharmacologic effects that resemble morphine, except it may be associated with less nausea and vomiting. The average dose is 2 mg (SC or orally) and this would be expected to last 6 to 8 hours. The oral-to-parenteral potency ratio is comparable to that of oxycodone and codeine. Levorphanol may be crushed so that it can be administered via nasogastric tube. It is occasionally useful in cancer patients who feel nauseated by morphine and who benefit from the longer-lasting effect, although it has largely been superseded by oxycodone and OxyContin.
Preparations

Levorphanol tartrate (Levo-Dromoran) injection, 2 mg/mL; tablet, 2 mg.
Methadone
Methadone is the only opioid with prolonged activity not achieved by controlled release formulation. It is a synthetic opioid with properties similar to those of morphine. Sedation and respiratory depression can outlast the analgesic action. In addition to its mu agonist effect, it is an NMDA inhibitor and an inhibitor of serotonin and norepinephrine reuptake. This is thought to confer real benefit in terms of reducing tolerance, a property that can be useful in opioid rotations (see Chapter 32). Abstinence symptoms are said to be less than morphine, and because of this and its long duration of action, it is used for detoxification or maintenance treatment for opioid addicts. For pain relief, oral doses may vary from 2.5 to 15 mg, parenteral doses from 2.5 to 10 mg and, for addict maintenance, 40 to 100 mg daily. After an oral dose, analgesia occurs in 30 to 60 minutes. After a parenteral dose, analgesia occurs in 10 to 20 minutes, with peak effects in 1 to 2 hours. The drug is eliminated slowly, which makes it liable to accumulate. Rapid titration (up and down) is not possible, so that this drug is best reserved for patients with stable pain. Although methadone is cheap, many physicians are uncomfortable prescribing it for outpatients because of its lack of titratability.
Preparations

Methadone hydrochloride (Dolophine) injection, 10 tablets, 5 and 10 mg (40-mg specialized dose for opioid addiction); oral solutions, 1, 2, and 10 mg/mL.
Fentanyl
This is a phenylpiperidine that is 50 to 80 times as potent as morphine. It can be used as an analgesic (2 to 10 µg/kg) or anesthetic (20 to 100 µg/kg). Onset after parenteral administration is very rapid. Maximal analgesia and respiratory depression may not peak until 20 to 30 minutes after IM injection or several minutes after IV usage. Fentanyl may also be given intrathecally, epidurally, via mucous membranes, or through the skin. Transdermal fentanyl is extremely useful as a treatment for chronic pain, especially cancer pain, when the oral route cannot be used. Several fentanyl derivatives (sufentanil, alfentanil, and remifentanil) are used in anesthetic practice but not in pain practice.
Preparations

Fentanyl citrate (Sublimaze) injection, 50 µg/mL.

Fentanyl transdermal system (Duragesic) patches, 25, 50, 75, and 100 µg/hr.
Buprenorphine
Buprenorphine is a highly lipophilic, semisynthetic opioid with partial activity at the mu receptor and very little activity at the kappa and sigma receptors. It has a high affinity but low intrinsic activity at the mu receptor. It has qualitatively similar effects to morphine in terms of analgesia, CNS, and cardiovascular system effects. However, since it is a partial agonist, it has a pharmacologic ceiling. Buprenorphine 0.4 mg is the equivalent of 10 mg of morphine IM, but buprenorphine has a longer duration of action. The dose for analgesia is 0.3 mg IM or IV every 6 hours. After IM administration, initial effects are seen at 15 minutes with a peak at 1 hour. IV administration results in shorter onset and peak times. Sublingual doses of 0.4 mg produce effective pain relief.
Preparation

Buprenorphine hydrochloride (Buprenex) injection, 0.3 mg/mL.
Nalbuphine
Nalbuphine is an agonist–antagonist; the chief agonist effects are at the kappa site. Nalbuphine has a ceiling effect on analgesia and respiratory depression, and doses above about 30 mg have no further effect. Dysphoria due to sigma activation may occur. Sedative effects are similar to those of morphine. Sweating and headache may occur. The usual dose in the adult is 10 mg every 3 to 6 hours parenterally, when the onset of effect is 5 to 10 minutes and the duration of action is 3 to 6 hours.
Preparations

Nalbuphine hydrochloride (Nubain) injections, 10 and 20 mg/mL.
Tramadol
Tramadol is a synthetic, centrally acting analgesic with an unusual mode of action. It has weak opioid activity at mu, delta, and kappa receptors, with a 20-fold preference for the mu receptor. It also has nonopioid analgesic activity via norepinephrine and serotonin reuptake inhibition. In the United States, tramadol is available only as an oral preparation. It has a low potential for addiction and respiratory depression. Its main use is in mild to moderate pain, but it can be used to treat severe pain (usually together with other nonopioid analgesics) in patients who cannot tolerate standard opioids. It is usually given as 25 to 100 mg every 4 to 6 hours orally, but the maximum daily dose should not exceed 400 mg. Dosing is limited by side effects, especially dizziness and vertigo.
Preparations

Tramadol hydrochloride (Ultram) scored tablet, 50 mg.
Naloxone
Naloxone is an opioid antagonist with greatest affinity for the mu receptor but acting at all opioid receptors. Small doses given intravenously or intramuscularly either prevent or promptly reverse the effects of mu-receptor agonists. In addition to reversing analgesia, patients with respiratory depression show an increase in respiratory rate within 1 to 2 minutes. Sedative effects are also reversed and blood pressure, if low, returns to normal. The duration of action is 1 to 4 hours and the plasma half-life is about 1 hour. Abrupt reversal of narcotic depression with large doses of naloxone may result in nausea and vomiting, tachycardia, sweating, hypertension, tremulousness, seizures, and cardiac arrest. These effects are at least partially attributable to a sudden surge of sympathetic activity as is seen in opioid withdrawal states. Other side effects that have been reported include hypotension, ventricular tachycardia and fibrillation, and pulmonary edema.
To avoid these serious and potentially dangerous side effects, it is advisable to reverse the effects of opioids slowly with repeated small doses of naloxone, titrating the dose to effect. This can easily be accomplished by diluting one 0.4-mg ampule in 10 ml (0.04 mg/mL) and injecting 1 to 2 ml (0.04 to 0.08 mg) every 1 to 2 minutes. In this way, it is sometimes possible to reverse respiratory depression while retaining analgesia.
Naloxone is readily absorbed from the GI tract, but the drug is almost completely metabolized by the liver before it reaches the circulation. Parenteral administration is thus needed for systemic effects. The drug may be used orally to treat constipation, utilizing its localized effect on opioid receptors in the gut. Generally, doses range from 0.8 to 4.0 mg (2 to 10 ampoules) every 4 hours, four times, or until a bowel movement has occurred.
Preparations

Naloxone hydrochloride (Narcan) injections, 0.02, 0.4, and 1.0 mg/mL.
CONCLUSION
Opioids are the most effective analgesics known, which is not surprising, as we now know that endogenous opioids are responsible for natural analgesic states and that opiate drugs produce analgesia by binding to endogenous opioid receptors. Unfortunately, there are several barriers to their use, not the least of which is the risk of respiratory depression—a potentially lethal side effect of opioids. Another important barrier is the social stigma attached to opioids because of their use as recreational drugs. Careful education of healthcare providers, patients, and patients’ relatives is often needed to allow them to understand the therapeutic value of opioids and the difference between this use and recreational use.
The opioids are not benign drugs and should be used with knowledge of their complex actions and adverse effects. At the same time, they are essential tools in pain management and in medicine in general, so that an understanding of opioid effects is important.
SELECTED READING
Borsook D. Opioids and neurological effects. Curr Opin Anaesthesiol 1994;7:352–357.
Carr D, Lipkowski A. Mechanisms of opioid analgesic actions. In: Rogers MC, Tinker JM, Corrino BG, Longneckes DE, eds. Principles and practice of anesthesiology. St. Louis: Mosby–Year Book, 1993.
Cowan A. Mechanisms of opioid activity. Curr Opin Anaesthesiol 1992;5:529–534.
Fields HL. Pain. New York: McGraw-Hill, 1987:251–279.
Lambert DG. Opioid receptors. Curr Opin Anaesthesiol 1995;8:317–322.
Malan TP Jr. Opioid pharmacology in anesthesia pain management. ASA refresher lectures. 2000:422.
Physicians Desk Reference. Oradell, NJ: Medical Economics [annual].
Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, et al., eds. Goodman and Gilman’s the pharmacological basis of therapeutics, 9th ed. New York: McGraw-Hill, 1996.
Twycross RG. Opioids. In: Wall PD, Melzack R, eds. Textbook of pain, 3rd ed. New York: Churchill-Livingstone, 1994.
Wall PD, Melzack R, eds. Textbook of Pain, 3rd ed. New York:Churchill-Livingstone, 1994.

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