Tolerance

15 TOLERANCE Early historians of drug effects have noted that the responsiveness to a drug often decreased as a function of continued use [1]. Jean Mousin, physician to the King of France, observed (c.1612) that some individuals appeared to “sober up” while continuing to drink alcohol. However, the use of the term (acute) tolerance to describe these observations of Mousin; would have to wait for several centuries. In 1811, American Dr. Benjamin Rush observed a change in sensitivity to alcohol with chronic heavy drinking. It wasn’t until 50 1 years later that Canadian W. Canniff wrote on these effects of alcohol on humans and attributed these observations to the development of tolerance. English physiologist E.H. Starling (c.1923) described the features of acquired tolerance, and its relationship to heavy drinking and that some individuals could consume a dose that would cause death in others. Tolerance is the body’s ability to adapt or acclimate to the effect(s) of a drug. A larger dose of the drug is required over time to achieve the initial or same effect of the drug at the previous dose due to a progressively decreased responsiveness to the drug. This is an important consideration in the investigation of deaths involving alcohol, opioids, and sedative hypnotic drugs (e.g., GABA agonists). Tolerance can be divided into two types; innate and acquired. Innate tolerance is a genetically determined sensitivity or lack of sensitivity to a drug which is observed upon the first administration. Acquired tolerance may be categorized as physiological or adaptive (behavioral). Physiological tolerance may be further subcategorized into pharmacokinetic or metabolic and pharmacodynamic relating to a change in the receptor or its response to the drug. Pharmacokinetic tolerance is generally achieved via induction of enzyme(s) responsible for the metabolism of the target drug. This may occur through self-induction of enzymes; for example, repeated use of phenobarbital will induce liver P450 expression and thereby decrease the half-life of phenobarbital. This induction will result in increased doses of phenobarbital to

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achieve the same steady-state concentration. The coingestion of another drug may cause enhanced metabolism of the target drug so that the patient “appears” to become tolerant to the standard dose. Genetic polymorphisms may cause increased metabolism, thus also causing the patient to “appear” to be tolerant to the standard dose. Another type of physiological tolerance is pharmacodynamic. This tolerance is secondary to receptor responses after repeated drug dosing. The change in receptor response may be due to (1) decrease in the number of receptors (downregulation), (2) reduction of “firing” of the receptor (desensitization), or (3) structural changes in the receptor (“receptor shift”). Adaptive tolerance is another category of acquired tolerance. These are learned compensatory actions to accommodate to the effects of a drug. For instance, the lack of visible signs of intoxication with high ethyl alcohol concentrations is one of the most well-known examples adaptive tolerances; albeit there is a pharmacokinetic component as well. Environmental cues may also impact tolerance. Rats made tolerant to doses of morphine in an environment were found to lose analgesic tolerance in a novel environment [2]. This conditioned tolerance follows Pavlovian principles in which if the environmental cues are removed, there will be an enhancement of the pharmacological effect of the drug [3,4]. There are several misconceptions in regards to tolerance to drugs: (1) a drug tolerant individual is tolerant to all the effects of the drug, (2) tolerance develops uniformly across all behaviors or effects or at the same time, (3) drug tolerance once gained remains without change, and (4) drug tolerance confers immunity to a lethal intoxication from the drug. Ethyl alcohol is one of the most commonly seen substances in forensic toxicology and at times the interpretation of lethal intoxications are challenging. A fatal intoxication from ethyl alcohol can occur when blood concentrations rise to 0.40 1 g% in healthy individuals; however, tolerance to ethyl alcohol can be quite profound. Extremely high alcohol concentrations in patients who have survived have been reported; Johnson et al. [5] describes a 24-year-old female patient admitted to the emergency department who was grossly intoxication, with an initial serum alcohol concentration of 1.51 g% and O’Neill et al. [6] describes a 30-year-old male who was found comatose and was admitted to the emergency department with a blood alcohol concentration of 1.50 g% and with very aggressive medical intervention survived the event. Hammond et al. [7] reported a case of a woman with an extremely high concentration of ethyl

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alcohol. She had a concentration of 0.780 g% after being admitted to the emergency room following a motor vehicle accident. Three hours postadmission, her alcohol concentration was 0.520 g% and 11 hours later she was discharged from the hospital, fully coherent, with normal neurological examination and she demonstrated no signs of gross intoxication. Her alcohol concentration was 0.190 g% at discharge. Urso et al. [8] studied 76 subjects seen in an emergency department; who had admitted recent drinking. Sixty-five of these subjects had measurable alcohol concentrations ranging from 0.120 to 0.54 g%, with a mean value of 0.268 g%. All subjects were independently evaluated by two physicians and all were deemed clinically “nonintoxicated.” Perper et al. [9] evaluated 110 consecutive alcoholics entering a detoxification program. Fifty-four of the patients had blood (serum) alcohol concentrations of 0.20 g% or higher. Twenty four percent (n 5 13) of these patients exhibited no signs of clinical intoxication; 10 of these patients had blood (serum) alcohol concentrations of 0.35 g% or higher. Of this cohort, five showed a normal speech pattern, eight were ability to undress themselves without difficulty, and three had normal vision, as determined by the clinicians, and adequate verbal comprehension. These authors, as well as several others [10 12] have described patients who have developed significant tolerance to the intoxicating and potentially lethal effects of ethyl alcohol ingestion. As with alcohol, continued use of barbiturates, hallucinogens, other hypnotics, minor tranquilizers, and stimulants; tolerance has also been shown to occur. Tolerance does not develop at an equal rate to all effects of these drugs [13]. The development of tolerance to the effects of these drugs also varied between animal species and man. In general, tolerance in humans to barbiturates occurs between 30 and 80 days, with hallucinogens (LSD, psilocybin, dimethyltryptamine) 6 14 days and with stimulants (amphetamine) 14 days. Gygi et al. [14] found development of tolerance, from the pretreatment with escalating doses of methamphetamine, to appetite suppression, hyperthermia, and hypertension. The authors believed the mechanism was related to a reduced distribution of the drug into the brain. However, Thomas and Kuhn [15] findings suggest that tolerance does not develop to the hyperthermic effects of methamphetamine. In addition, more recent data suggest that the developed tolerance to the neurotoxic effects of methamphetamine is related to pharmacodynamic changes; reductions in dopamine transporter uptake activity and dopamine receptor response [16,17].

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Tolerance to cocaine-induced convulsions after 13 days of use of subconvulsive doses of cocaine [18] and 13 35 days of cocaine dosing to the local anesthetic and stimulant effects has been demonstrated in cats [19]. Mendelson et al. [20] evaluated tolerance to the cardiovascular and subjective effects of cocaine by comparing the acute effects of cocaine in occasional users as compared to cocaine-dependent men. They found no pharmacokinetic differences in the two groups, that is, peak plasma concentrations were equivalent over the 2 hours measurement period. The authors did observe tolerance to the cardiovascular effects, that is, a lower heart rate, lower systolic and diastolic blood pressure in subjects who had a history of prior chronic use of cocaine, as well as a decrease in the reported “euphoria” and “high” in the chronic user group. Similar to methamphetamine, pharmacodynamic tolerance to cocaine is mediated by reduction in dopamine transporter system, thereby reducing cocaine’s ability to increase extracellular dopamine thus attenuating its euphoric effects [21,22]. Opioids are another class of drug that is well-known for the development of tolerance; most notably to the euphoric, analgesic, and central nervous system (respiratory) depressant effects. Although, increases in opioid dose may be due to a buildup of tolerance to the analgesic effects; desensitization of the receptor(s), a decrease in the number of binding sites on the receptor [23], and/or reduced interaction with P-glycoprotein efflux transporters [24] or, it may be a consequence of increased pain due to disease escalation. Pain can act as an antagonist to the central nervous system, especially the respiratory, depressant effects of opioids. The analgesia achieved may remove the stimulatory effect of the pain, thus leading to unopposed opioid-mediated respiratory depressant effect, and could result in significant somnolence and respiratory depression [25]. Long-term use of opioids may also lead to a paradoxical response in that the patient receiving opioid treatment for pain may become more sensitive to painful stimuli. This state of nociceptive sensitization is called opioid-induced hyperalgesia [26], opioid-induced abnormal pain sensitivity [27], or paradoxical hyperalgesia [28]. The mechanism of opioid-induced hyperalgesia is not fully understood. Silverman [29] and a review by Lee et al. [30] suggests that sensitization of pronociceptive pathways may be a possible mechanism; involving in part the excitatory neurotransmitter, N-methyl-D-aspartate. Tolerance may complicate the interpretation of opioid blood concentrations; a concentration may be tolerable in one

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individual whereas it may prove to be lethal in another. Methadone is a common example of a drug where overlapping drug concentrations (Table 15.1) in acute overdoses and patients who are on a chronic dosing regimen, where tolerance has developed [31]. Thus, making the determination of methadone intoxication very difficult based solely on drug blood concentrations. Tolerance develops at different rates for various drug effects. Although long-term use of opioids leads to the development of significant tolerance to its various effects, they may develop at different rates [32]; tolerance to the analgesic, euphoric, respiratory depressant, and sedative effects develop rapidly as compared to the minimal development of tolerance to constipation and miosis. File [33] reviewed the evidence of tolerance of benzodiazepines, GABA agonists, in animals (mouse and rat). She found the rapid development of tolerance (3 5 days) to the sedative effects and from 5 days of treatment to the anticonvulsant effects of benzodiazepines. However, tolerance was not found, after a 7 15 day treatment period, to the anxiolytic effects of the benzodiazepines; although it was observed in a social interaction test after 25 days. Fine suggests that the observed differences in rates of tolerance were a function of the experimental design and not the measured behavior. Vinkers and Olivier [34] noted that tolerance to the sedative and anticonvulsant effects of the benzodiazepines develops quite rapidly, whereas tolerance to the amnesic and anxiolytic effects does not develop to any appreciable extent. The tolerance to the sedative effects of the benzodiazepines studied appeared to be more prominent with benzodiazepines with a short half-life. Although a limitation in most studies was a limited duration of exposure to the drug. As for tolerance to the anticonvulsant effects, tolerance developed during the first few months of

Table 15.1 Overlapping Methadone Concentrations: Overdose Versus Maintenance Programs Methadone Concentration

Overdose (mg/L)

MTD Maintenance (mg/L)

Mean Range

0.28 0.06 3.1

0.11 0.03 0.56

Source: From Worm K, Steentoft A, Kringsholm B. Methadone and drug addicts. Int J Legal Med 1993;106:119 23.

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treatment with clobazam or clonazepam in 30% 50% of the epilepsy patients. Most studies have found there was minimal development of tolerance to the amnesic effects of the benzodiazepines; however, Cowley et al. [35] reported tolerance after chronic (4 98 months) alprazolam treatment to the sedative effects, but not the anxiolytic and suggested tolerance to shortterm memory effects. The authors did note that their study used a different memory test, as compared to others and the chronicity of the alprazolam use was significant, with a mean of over 4 years of treatment. The studies reviewed by Vinkers and Olivier on the anxiolytic effects of the benzodiazepines did not suggest the development of tolerance. Stoops and Rush [36] found evidence to suggest that there is some tolerance developed to the amnesic effects of triazolam but not zolpidem, another GABA agonist. Kleykamp et al. [37] evaluated zolpidem, and found that with chronic dosing (22 30 days) tolerance did not develop to the zolpidem-related impairments, including the amnesic effect. Tachyphylaxis or acute tolerance is an acute, sudden decrease in response to a drug after its administration; the onset may be within a matter of minutes during a single drug exposure. Tachyphylaxis has been observed with several classes of drugs. It is mediated by pharmacodynamics mechanisms; following a single dose of a drug or during repeated dosing over a short period of time. The most notable drug is ethyl alcohol. In 1919, Sir Edward Mellanby described the development of acute tolerance to alcohol [38]. He observed greater effect of intoxication when the blood alcohol concentration was rising as opposed to when they were declining (Fig. 15.1) at a given blood alcohol concentration. Mellanby suggested that this phenomenon may apply to other sedative hypnotics as well. Holland and Ferner [39] recently reviewed the evidence for

Figure 15.1 Blood Alcohol Concentration vs Intensity of Central Nervous System Effects.

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alcohol acute tolerance. They noted that the subjective intoxication and the willingness to drive was greater as the blood alcohol concentration was rising; that an individual felt less “drunk” during the postabsorptive phase of the alcohol elimination curve (decreasing blood alcohol concentration) as compared to the absorptive phase. Morris et al. [40] presents evidence to suggest that the faster the blood alcohol concentration increases the greater the acute tolerance; as indicated by subjective feelings of intoxication. Brodie et al. [41] first observed acute tolerance to hypnotic effects of thiopental; after a large dose of the thiopental, patients awoke at plasma concentrations that were significantly higher than those occurring after a smaller dose in the same patient. Dundee et al. [42] observed that British anesthetists gave about twice the dose of thiopentone (thiopental) for surgical procedures as did American anesthetists; the larger the dose the higher the blood concentration upon awakening. Brand et al. [43] demonstrated that rapidly increasing thiopentone concentrations were needed to produce a constant state of anesthesia. The authors monitored a specific EEG pattern, in 31 surgical patients, to assess the level of anesthesia and the need to infuse more thiopental to maintain the plateau state of anesthesia. Ellinwood et al. [44] examined the effect of three different doses of pentobarbital on the performance of a complex psychomotor task. The authors found performance impairment was up to four times greater at 20 minutes than at 2 hours postdosing. Although the impairment was greatest in the performance of the complex task at 20 minutes, the pentobarbital maximum blood concentration was not reached until 2 hours; thus suggesting the role of acute tolerance in the measured task. Ellinwood et al. [45] evaluated acute tolerance of diazepam and pentobarbital following a single dose by measuring tracking deviation. They observed a substantial recovery of predose functionality within minutes to a few hours. Wong et al. [46] observed that the ability of diazepam to cause sleep was significantly reduced after single dose of diazepam or lorazepam. They suggested that the development of the acute tolerance may be due to a change in receptor sensitivity to the benzodiazepine. Albrecht et al. [47] studying the pharmacokinetics and pharmacodynamics of midazolam and found indications of acute tolerance to the hypnotic effects of this benzodiazepine; after a relatively short exposure time of 1 2 hours. Coldwell et al. [48]

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evaluated the development of acute tolerance to motor control effects of midazolam. They observed initial impairment of motor control by midazolam. They studied 40 subjects who received an initial bolus of midazolam, followed by a continuous infusion of the drug. However, in spite of rising blood concentrations of midazolam, the authors observed an improvement of motor control skills. They concluded that this was due to the development of acute tolerance. Ihmsen et al. [49] studied the rapid development of acute tolerance to the hypnotic effect of midazolam. The authors suggested possible mechanisms for the acute tolerance as downregulation in the GABAA or receptor site adaptation by alteration of the receptor subunits. Fischman and Schuster [50] reported that the cardiovascular and euphoric effects of cocaine declined more rapidly than the decrease in cocaine blood concentration after a single dose; they opined that this may be suggestive of the development of acute tolerance. Ambre et al. [51] study demonstrated the occurrence of acute tolerance toward the cardiovascular and subjective effects of cocaine following intravenous administration. Foltin and Fischman [52] found evidence to suggest the development of acute tolerance to the cardiovascular and subjective effects of cocaine in users who either smoked cocaine or administered the drug intravenously. Foltin and Haney [53] studied the effect of insufflated cocaine and found this administration route also lead to acute tolerance of the cardiovascular and subjective effects of cocaine. The development of acute tolerance to the subjective effects of cocaine, that is the “high,” explains the reason why many cocaine users find that repeated dosing fails to produce this desired effect. Tachyphylaxis is observed in other commonly encountered drugs; antidepressants (monoamine oxidase inhibitors and selective serotonin reuptake inhibitors) [54], fentanyl [55], methylphenidate [56], nicotine [57], nitroglycerin [58], and ranitidine [59]. Long-term exposure to one drug often results in the development of tolerance to the effects of other structurally similar drug in the same pharmacological class. This overlapping of tolerance is termed “cross-tolerance.” Opioids, benzodiazepines, hallucinogens, and phenethylamines are commonly encountered drug classes that exhibit cross-tolerance. However, crosstolerance is rarely complete, developed for all drug effects and the degree of cross-tolerance varies between structurally similar drugs. The substitution of initial drug, with another in its class

Chapter 15 TOLERANCE

may result in a lesser response; especially if compared to the naı¨ve patient. The incomplete cross-tolerance is due to subtle differences in the molecular structure of the drug and/or its interaction at the receptor. Incomplete opioid cross-tolerance to the analgesic and other side-effects may also be accounted for, at least in part, by multiple opioid (mu) receptor subtypes [60]. Opioid rotation takes advantage of this variable cross-tolerance; it is used in patients who may become tolerant to one opioid by switching to another opioid [61]. Attempts to address variable opioid crosstolerance have driven the development of various “equianalgesic potency” conversation tables [62,63]. These conversion tables provide ratios of the dose of the current opioid to the one being switched to, to provide an equivalent analgesic effect. However, clinical observations suggest that there may be differences between the published equanalgesic dose and the effective conversion ratio [64]. Although the ultimate decision is between the clinician and the patient, some practitioners suggest starting with 50% 75%, or sometimes lower, of the published equanalgesic dose of the new opioid to compensate for incomplete cross-tolerance and individual variation, and then titrate for effect. Additional dose adjustments may also be necessary to compensate for genetic polymorphisms in drug metabolism enzymes (e.g., P450), drug drug interactions impacting drug metabolizing enzyme systems (induction or inhibition), hepatic, or renal insufficiency. Several studies have addressed switching from morphine or hydromorphone to methadone [65 67]. Methadone appears to have a higher than expected potency during chronic therapy as compared with published equanalgesic doses for acute dosing [68]. Some authors suggest starting with 10% 25% of the published equanalgesic dose of methadone and titrating slowly, given methadone’s long half-life, upward to achieve adequate pain control. A few studies have examined the opposite rotation, that is, switching from methadone to an alternate opioid. Walker et al. [69] evaluated cancer patients who were on long-term methadone treatment and switching them to an alternate oral opioid. They were able to achieve stable dosing in 2.5 2.6 days (mean days); IV versus oral methadone, respectively. Tolerance to the sedative and anticonvulsant effects of benzodiazepines is well-known [34]. Aranko and Mattila [70] demonstrated the development of cross-tolerance between diazepam and lorazepam to various psychomotor functions in humans. Cross-tolerance to the anticonvulsant effects of alprazolam and lorazepam in chronically treated mice has been observed [71].

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Tolerance to D-diethylamide lysergic acid and cross-tolerance to a structural analog, D-2-bromo-lysergic acid diethylamide was noted back in the late 1950s [72], along with cross-tolerance to another hallucinogen, psilocybin [73]. A number of phenethylamine compounds have been observed to develop tolerance to their various drug effects. Smith et al. [74] evaluated the potential development of tolerance and cross-tolerance to the hallucinogenic effects of two structurally different drug classes; two phenethylaminederived compounds (2,5-dimethoxy-4-iodoamphetamine and 2,5-dimethoxy-4-propylthiophenethylamine) and two tryptamine-derived compounds (N,N-dipropyltryptamine and N,N-diisopropyltryptamine). The authors found that the hallucinogenic phenethylamine compounds did develop tolerance, individually and to each other with daily dosing, whereas the tryptamine compounds did not demonstrate tolerance in the mouse model utilized. Kandel et al. [75] demonstrated cross-tolerance, in milk intake suppressant effects in rats, between D-amphetamine and D-methamphetamine, but not between D-amphetamine and D,L-fenfluramine. In a similar study, Zacny et al. [76] demonstrated the development of cross-tolerance between D-methamphetamine and D,L-methylenedioxymethamphetamine, whereas cross-tolerance was not shown to develop between methamphetamine and D,L-methylenedioxyamphetamine. Tolerance and cross-tolerance in chronically treated rats has been demonstrated with amphetamine and pseudoephedrine [77]. The authors do note that a very large amount of pseudoephedrine would be needed in humans to equate to the doses used in their rat study. Cross-tolerance, to one degree or another, to drug effects has also been demonstrated in structurally unrelated compounds. Chronic ingestion of alcohol will lead to tolerance to alcohol induced hypothermia, ataxia, and narcosis. Cross-tolerance was observed to these effects by barbital in alcohol-habituated subjects, however, cross-tolerance was not observed in pentobarbital-induced hypothermia or ataxia [78]. Leˆ et al. [79] found that there was full cross-tolerance between alcohol and pentobarbital in the moving-belt and two-way shuttle-box avoidance tests with rats that were chronically treated with one or the other drug. While chronic treatment with chlordiazepoxide allowed for full cross-tolerance to alcohol or pentobarbital, there was only partial cross-tolerance to chlordiazepoxide following chronic exposure to alcohol or pentobarbital. Peltier et al. [80] studied the effect of chronic treatment of

Chapter 15 TOLERANCE

D-amphetamine or methamphetamine on the cross-tolerance to the discriminative and/or reinforcing effects of cocaine in rats. The authors found that chronic treatment with sympathomimetic drugs, such as amphetamine and methamphetamine, produced cross-tolerance to the discriminative and reinforcing effects of cocaine. Allan et al. [81] suggests that there is a degree of cross-tolerance between phenobarbital and flunitrazepam. They demonstrated with the chronic treatment with phenobarbital that there are some adaptive changes on the GABA receptor. Flaishon et al. [82] examined the effect of 2 weeks of chronic administration of diazepam to the sensitivity to the anesthetic gas isoflurane and vice versa in mice. The authors observed that chronic treatment with diazepam or prolonged exposure to isoflurane would reduce the sensitivity not only to each drug individually, but each other as well. Tolerance and cross-tolerance is variable within drug classes. It is not seen for all effects of a drug and may develop at different rates. Eventually, a maximal response of a drug effect is obtained and further increase in dose does not produce a greater effect. This is known as the “ceiling effect.” Ceiling effect reflects the therapeutic limitation of some drug classes. Doses above those needed for the ceiling effect of the desired action, for example, analgesia, may cause other undesirable, often toxic drug side-effects. Nonsteroidal antiinflammatory drugs and mixed agonist antagonist opioids, such as nalbuphine and a partial agonist buprenorphine are examples of drugs which exhibit a ceiling effect. Laska et al. [83] and Seymour et al. [84] compared various doses of ibuprofen (400 800 and 200 600 mg, respectively) in providing analgesia for postoperative dental pain. Laska reported an analgesic ceiling for ibuprofen is 400 mg/dose (1200 mg/day); with a 2400 mg/day effective dose for inflammation, without any additional pain relief. Seymour et al. corroborated Laska’s work reporting they found no significant increase in analgesic efficacy of ibuprofen in doses above 400 mg. Skoglund et al. [85] compared two doses (1000 and 2000 mg) of acetaminophen (APAP), APAP 1000 mg/60 mg codeine combination and placebo in a single dose, double blind study on dental pain over a 6-hour period. The authors found that the APAP with codeine combination was superior to all formulations studies and that the ceiling dose for analgesia was 1000 mg of APAP. For the mixed agonist antagonist opioid nalbuphine, acting at the kappa and mu opioid receptors, the ceiling effect is beneficial [86]. Once the maximal blood concentration is achieved,

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further increases in dose do not increase it analgesic properties, and importantly does not increase the risk of significant respiratory depression. A neonate who was accidentally administered a dose 10 times higher than needed only experienced prolonged sedation without respiratory compromise. Buprenorphine, a partial agonist which exerts significant action at the mu opioid receptor, also exhibits a ceiling effect to the respiratory depressant effects. Dahan et al. [87] compared two intravenous doses, 0.2 and 0.4 mg, of buprenorphine in 20 total subjects, 10 for each dose over an 8-hour period. The authors reported that the analgesic effect increased significantly in the higher dose, whereas the onset and magnitude of the respiratory depression was similar. They concluded from this study that buprenorphine displays a ceiling effect for respiratory depression but not for its’s analgesic properties. However, buprenorphine can block the effects of full opioid agonists and can precipitate opioid withdrawal symptoms if administered to an opioid-addicted individual while a full agonist is on board. Gustavsen et al. [88] studied concentration-effect relationship between blood amphetamine(s) and impairment in Norwegian drivers abusing amphetamine(s). A police physician evaluated the subjects for impairment. The authors noted a positive relationship between blood amphetamine(s) concentrations and impairment. However, this relationship reached a ceiling at blood concentrations of 0.27 0.53 mg/L. The development of tolerance is not a permanent result of long-term drug usage. After drug exposure is terminated, or significantly reduced, tolerance is lost. Induced metabolic enzymes return to normal status and desensitized receptors return to original levels of function. The termination of drug exposure may be due to voluntary cessation of use, for example, entering into a detoxification program or an involuntary cessation due to incarceration or hospitalization [89,90]. Individuals following a period of abstinence who return to using their “usual” dose of drug end up, in many cases, with a fatal outcome. Groot et al. [91] reviewed drugs deaths following incarceration in Ontario, Canada from 2006 to 2013, in which the vast majority was from opioids. They found there was an increase in risk of death from drug overdose after release from prison; with 10% of the drug deaths occurring within 1 year of release. The death rate was the highest immediately after release. The occurrence of a lethal drug overdose is the highest during the first couple weeks after release from incarceration; most likely due to reduced use or no drug consumption in prison and the loss of drug tolerance. Bird and Hutchinson [92] found in Scottish

Chapter 15 TOLERANCE

inmates, in custody for 14 or more days, drug-related deaths were seven times higher in the first 2 weeks after release as compared to the following 10 weeks. A search of the Australian National Coroners Information System for deaths among exprisoners from 2000 to 2007 was undertaken [93]. They found that about 50% of the deaths were classified as accidental drugrelated deaths. The majority of these deaths involved a combination of drugs; including alcohol, benzodiazepines, and opioids. Binswanger et al. [94] studied Washington state prisoners released from custody from July 1999 to December 2003. They found that the risk of death was 3.5 times higher in former inmates as compared to the general population of the state. During the first 2 weeks following release from incarceration for 2 weeks, the risk of dying for the former inmates was 12.7 times higher as compared to the general state population, with a markedly elevated risk of death due to drug overdose. Dumas and Pollack [23] reported that in fully tolerant (morphine) animals a drug holiday of nearly 6 days would be required in order to regenerate 50% of the animals intrinsic responsivity to morphine lost during the development of tolerance. Brinkley-Rubinstein et al. [95] studied fentanyl related overdose postrelease from incarceration in a Rhode Island (USA) Department of Corrections. They found that there was an increased risk of dying from a fentanyl related over within a year of postrelease. Abstinence is not the only reason for an individual to lose tolerance. In some cases, the individual may be taking multiple medications in which one may be an inducer of an enzyme that is responsible for the clearance of a drug that one has developed tolerance to. If that medication is discontinued, the induction will wane off, and now potentially allow the “tolerant medication” to rise to a toxic concentration; the reverse may also occur. Ruttenber et al. [96] studied 505 decedents of heroin overdoses, comparing those with high ethyl alcohol concentrations ( . 0.100 g%) to those with alcohol concentrations lower than or equal to 0.100 g%. They evaluated whether or not the combination of ethyl alcohol and heroin acted additively or synergistically, or whether ethyl alcohol interfered with the metabolism of heroin and thus prolonging the effect of the narcotic and/or whether ethyl alcohol consumption resulted in reduced tolerance to heroin. The authors found an inverse correlation between ethyl alcohol concentrations and heroin concentration; suggesting a dose response relationship between alcohol

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consumption and acute toxicity of heroin. They found no evidence of altered metabolism of heroin by coingestion of alcohol. The decedents who had consumed large amounts of alcohol prior to their death had used heroin less frequently in the time prior to their death. Thus suggesting that heavy alcohol use indirectly influences the overdose by virtue of less frequent heroin use, therefore lower tolerance to heroin by reduction in its use. Hull et al. [97] reported on the reversal of morphine tolerance by ethyl alcohol in a mouse model. In their study, they found that ethyl alcohol significantly and in a dose-dependent fashion, reduced the antinociceptive tolerance produced by morphine. The authors found that the reversal of morphine tolerance involved both the GABAA and GABAB receptors. However, they could not determine in their study whether or not the reduction in tolerance to morphine was due to direct action on the receptors or via modulation of GABA release. There is not a biochemical, histological marker, or laboratory test that will predict tolerance or degree of tolerance in an individual. The postmortem assessment of tolerance, like the interpretation of any postmortem toxicological/biochemical result, is dependent upon the decedent’s medical history including drug exposure history, pharmacodynamic characteristics of the drug(s), autopsy findings, and scene investigation; in conjunction with the toxicological test results. The analysis of hair has been proposed as a tool to assist in determining the chronic exposure to a drug, and thus the potential for the development of tolerance. Kronstrand et al. [98] investigated the use of hair analysis in the toxicological evaluation of heroin deaths. They evaluated 19 heroin overdose cases. The authors opined that the absence of opiate (morphine) detection in the companion hair sample suggested “first use” or occasional usage of heroin. Thus, the lack of tolerance could be a factor in the evaluation of the death. They concluded that the analysis of hair would be a useful adjunct to the conventional autopsy samples submitted for toxicological analyses. Paterson et al. [99] conducted a much larger study evaluating 286 coroner cases in the UK from 2004 to 2006, in which hair was collected in addition to routine specimens. They found that analysis of the hair provided useful information as far as the decedent’s drug history; acute use or chronic use and thus demonstrating tolerance or lack thereof. However, Kintz [100] cautions against the use of hair analyses to demonstrate the long-term exposure to the drug. His study (n 5 5) found target drug in the hair of decedents who were not exposed chronically

Chapter 15 TOLERANCE

to the drug. The study cohort did undergo extensive hair decontamination procedures, used to remove environmental contamination, prior to the analyses. Kintz suggests that contamination from aqueous sources (blood, putrefactive juices, sweat) that come into contact with the hair after death are more difficult to remove than external contamination from smoke or other environmental sources. Since drug metabolite would also be in these fluids, the identification of a metabolite in hair would not be very useful in differentiating long-term use versus contamination. A later study by Kintz [101] suggests that performing segmental hair analyses may assist in determining whether or not contamination occurred. He opined that if multisectional analyses demonstrated homogenous test results, that it may be indicative of external contamination. Chronic use or tolerance to a drug does not necessarily immune the user from death. The decedent may have used more drug than he/she had developed tolerance to and/or may have ingested other drugs which could have an additive or synergistic effect. Since cross-tolerance with many drugs is not on par, tolerance to one drug in a pharmacological class does not provide protection from the toxic effects of its chemical cousin.

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