Drugs Pertinent to Workplace Testing

Of all the Opoids in use, a relatively small subset is pertinent to workplace testing. This includes codeine, hydrocodone/hydromorphone, heroin, methadone, morphine, and oxycodone. Even of this list, most of these drugs pertain to extended workplace panels or testing done in medical professionals or other special populations. Federally regulated workplace drug testing only involves morphine, codeine, and heroin as analyzed by 6-acetylmorphine (6-AM)    and remains the case even in the proposed relations of April 13, 2004. The following discussion covers a review of pharmacology and pharmacokinetics of the most pertinent drugs to workplace testing.

Codeine

One of the most extensively used Opoids, codeine is used in the management of mild to moderate pain and as an anti-tussive. Codeine is a mixed agonist/antagonist of µ and δ receptors. It is produced both commercially from morphine and is a natural component of opium. Single oral dosages range from 15 to 60 mg, with total daily dosages typically from 60 to 240 mg. Codeine is available in numerous formulations and is indicated for analgesia and as an antitussive. Preparations include tablets syrups, and solutions for subcutaneous injection. Following oral dosage, approximately 10 to 20% is excreted in the urine within 24 h. Three days after codeine use, only morphine was present in urine and was identical to morphine or heroin use. 95% of a single dose was eliminated in 48 h.

The serum half-life for codeine is approximately 3 h. Maximum serum concentrations of 0.126 and 0.256 mg/L after a 60- and 120-m dose respectively, have been reported. Saarialo Kere et al. reported 0.105 mg/L serum levels 1.5 h after a 100 trig oral dose. One hour after a 60-mg dose serum levels were measured at 0.11 mg/L. Within 60 mitt of a 65-mg intramuscular AMP dose, peak plasma concentrations were measured at a mean of 0.264 mg/L. Approximately 10% of the dose is O-demethylated by cytochrome P450 2D6 (CYP2D6) to form morphine. Seven percent of Caucasians and 50% of Chinese subjects have nominally functional polymorphisms of CYP2D6 and are poor metabolites of codeine.

Formation of morphine contributes to the analgesic effects of codeine and polymorphisms of GYP2D6 have been attributed to some of the inter-individual variation in human response to codeine. N-demethylation to norcodeine and glucuronidation to form both codeine glucuronide and morphine-glucuronide accounts for other metabolizes. Morphine predominates in the early phase of excretion, but over 20 to 40 h morphine conjugates tend to prep dominate.

Heroin/6-AM

Diacetylmorphine was originally synthesized in 1874 and marketed by the Bayer company in 1898. Periodically, increased interest has arisen in the use of heroin for pain management in terminal illnesses. Currently, it is still a Schedule I drug with no known legitimate medical usage and is a significant drug of abuse. Peak heroin concentrations are observed typically within minutes of dosage by intravenous IV, IM, or insufflation routes. Concentrations after intranasal and IM administration are reported to decline in a first order logarithmic manner with mean elimination half-lives (in hours) of 0.09 (6 mg intranasal), 0.07 912 mg instranasal), and 0.02 (8 mg IM).

Metabolism is via deacetylation to 6-AM and then to morphine, which is then conjugated for excretion. Heroin deacetylation is catalyzed by blood esterases and spontaneous hydrolysis of 8-AM is reported in biological fluids. Peak 6-AM concentrations are observed 5 to 10 min after heroin administration with mean elimination half-lives (in hours) reported as 0.18 (6 mg intranasal), 0.22 (12 mg intranasal), and O. l9 (6 mg IM). Morphine concentrations peaked within 1 h of dosage and mean elimination half-lives for the same dosage scheme were 1.5, 2.8., and 3.6 h. Following an IV, O-mg dose of heroin, approximately 45% of the dose was recovered in the urine over 40 h.

Recovery was as 4.2% morphine, 38.3% conjugated morphine, 1.3% 6-AM, and 0.1% parent heroin. Unconjugated morphine was seen early in the profile, with very little found after 12 h. Urinary elimination half-lives averaged 0.6, 4.4, and 7.9 h for 6-AM, morphine, and conjugated morphine, respectively, in volunteers given 6 mg of heroin IM fit.

Hydrocodone/Hydromorphone

Hydrocodone dihydrocodeinone, is a semisynthetic narcotic prepared from codeine that is more toxic than codeine. Hydrocodone is available in Syrups and tablets with recommended dosages for adults of 5 to 10 mg 3 to 4 times a day and for children 0.6 mg/kg body weight, divided into 3 or 4 doses. An effective antitussive agent, hydrocodone also produces a number of Opoid effects such as central nervous system depression, miosis, and an addiction liability. It has been suggested that most of the Opoid effects of hydrocodone actually occur from the hydromorphone formed during metabolism.

Hydromorphone, dihydromorphinone, is a semisynthetic narcotic and an agonist Opoid. Hydromorphone, used therapeutically since 1926, is available in tablets of 2, 4, or 8 mg; in syrups of 1 and 5 mg/5mL; in solutions of 1, 2, 4, or 10 mg/mL for IV, IM, subcutaneous or intrathecal administration; and also in 3-mg rectal suppositories. A controlled-release formula is available in Canada but not in the United States. Hydromorphone is used in postoperative pain management and in the treatment of some cancer pain.

Hydromorphone’s medicinal use increased 1996 during the time period of 1990 to l996. During the same time penod, the reports of abuse decreased by 15%. During metabolism, hydrocodone is O-demethylated to hydromorphone, N-demethylated to form norhydrocodone, and C6-keto reduced to form approximately equal amounts of 6α- and 6β-hydrocol. CYP2D6 is involved in the metabolism of hydrocodone to hydromorphone. The maximum concentration of hydromorphone seen after a dose of hydrocodone varies (greater than 5-fold) between individuals in correlation to their CYP2D6 function. Poor metabolites excreted significantly more of the unchanged hydrocodone in their urine.

Peak plasma concentrations of hydromorphone occurred 1 to 2 h after a dose of hydrocodone. This potential increase in hydrocodone concentration does not seem to cause a marked difference in the pharmacological effects of a dose of hydrocodone. Gone and Darwin found 14% of the total urinary recovery of a Hung dose was hydromorphone, 20% was the N-demethylated metabolize norhydrocodone, and 14% was the product of C6-sketo reduction. Oral hydromorphone is 5 to 7 times more potent than morphine, i.e., a 10-mg dose of morphine is equally analgesic to a 1.5- to 2-mg dose of hydramorphone. This ratio is lowered in those who are Opoid-tolerant to 3:1 to 5:1.

When administered IV, hydromorphone is 8.5 times more potent in its analgesic efficacy than morphine and is 60 times more potent than meperidine when administered epi-durally. Hydromorphone by IV administration has a rapid onset of effects within 6 min. a short time to peak effects, within 10 to 20 min. and a relatively short duration of action of between 3 and 4 h. Dizziness, flushing sensation, sedation, mental confusion, anxiety, fear, dysphoria, nauseas and vomiting are adverse effects of hydromorphone. A log-linear dose-effect relationship for analgesia and respiratory depression was observed across the dose range of 0.5 to 4 mg in bath postoperative patients and normal volunteers.

In patients receiving large doses of systemically administered hydromorphone for pain treatment, neuro-excitatory side effects such as allodynia, myoclonic jerks, and seizures can occur caused by the hydramorphone~-glucuronide (HUGE metabolite and may warrant switching the patient to a structurally dissimilar Opoid (e.g., methadone or fentanyl). The onset of effects is delayed to 30 to 180 min after non-IV administration of hydromorphone. Ritschel et al. found that it took 60 min for 95% of the hydromorphone in a tablet to be released, and 8 h for 60% of the hydromorphone in a cocoa butter suppository to be released.

Average terminal elimination half-lives for the various administration routes are 2.4 to 3 h for IV administration, 4.1 h for oral administration, and 3.8 for rectal administration. Coda et at found peak plasma concentrations of 0.00803, 0.01411, and 0.02186 mg/L after IV administration of 10-, 20-, and 40µg/kg doses, respectively. Mean peak plasma concentrations of 0.022 mg/L after oral administration of 4 mg hydromorphone occurred at 1 h. Cancer patients given an average daily dose of 48 mg my of controlled release and immediate-release hydromorphone showed no significant difference in the steady-state hydromorphone and H3G concentrations. After administration of the controlled-release product, Cmax of hydrocodone and H3G were 0.01776 mg/L and 0.40169 mg/L, respectively.

Administration of immediate-release drug resulted in Can of 0.0197 mg/L hydrocodone and 0.36774 mg/L H3G. The pharmacokinetic profiles of immediate-release and controlled release hydromorphone showed no significant differences over this dosage range. Babul et al. again examined the pharmacokinetic profile of controlled-release hydromorphone and found similar profiles when comparing children and adults being treated for pain.

The peak concentration of hydromorphone occurs significantly later with controlled-release dosing, 12 h compared to 0.8 h for immediate release, but maintains at 50% of peak concentration for significantly longer, 31 h compared to 1.6 h. Similarly, controlled-release hydromorphone produced analgesic effects that peak later and last longer. Hydromorphone undergoes first-pass elimination following oral administration. Primarily metabolized to H3G, the mean steady-state molar ratio of H3G to hydromorphone was 27:1 in adult cancer patients.

Two minor metabolites of hydromorphone, dihydromorphine and dihydroisomorphine have demonstrated pharmacological activity but their contribution may De minimal because of the small amount formed. Hydromorphone is primarily excreted in the urine as a glucuronide conjugate (35%) with minor amounts of dihydromorphine and dihydroisomorphine corrugate (2%), and unchanged drug (6%) being found. The majority of a dose is excreted in the first 24 h with the free and conjugated drug reaching undetectable levels after 8 and 48 h, respectively.

Methadone

Methadone was developed during World War II as a substitute for morphine and heroin. It became available for clinical use in the United States in 1947. Twenty years before methadone maintenance began, methadone was first used by the Public Health Service facility in Lexington, Kentucky to gradually withdraw Opoid addicts. In 1965, methadone was formally introduced as a substitution treatment for Opoid dependence. Methadone maintenance programs still remain controversial 30 years later.

Replacing heroin with methadone has not cured all of the problems associated with addiction Overdose deaths, the use of illicit drugs, infections, and crime is still present; diversion of methadone provides an illicit source. Methadone maintenance programs have, however, significantly reduced the number of deaths, reduced the occurrence of infection with HIV, and have decreased the amount of criminal behavior in the community.

Methadone, indicated for the relief of moderate-to-severe pain, is approximately equipotent to morphine as an analgesic when administered parenterally. Commercially available under the trade name Dolophine, methadone is supplied as the hydrochloride salt of the racemic mixture. The pharmacological activity is almost entirely due to (R)-methadone. With a 10-fold higher affinity at µ and δ Opoid receptors, (R)-methadone has been shown to have 50 times the analgesic activity of methadone in human and animal studies. (R)-Methadone prevents the occurrence of Opoid withdrawal symptoms while (S)-methadone is ineffective. For oral usage, methadone is available in tablets of 5 or 10 mg, diskettes of 40 mg, or as syrup of 1, 2, or 10 mg/mL. A 10 mg/mL solution is also available for parenteral Erection.

The maximal direct Opoid effects occur approximately 3 h after methadone ingestion, causing sedation, altered perception and response to pain, and general central nervous system depression. Although 50 mg or less has proven fatal in non-tolerant adults, as much as 180 mg/day may be used in methadone maintenance programs, and in rare incidences up to 780 mg/day have been required to prevent illicit Opoid use in some patients. Most deaths that are related to methadone administration occur during the first few days of methadone maintenance treatment, when fatal respiratory depression is a risk.

After oral administration, methadone is rapidly absorbed from the gas trointestinal tract and is detectable in the blood within 30 min. Oral bioavailability of total methadone varies from 41 to 9946 Bioavailability after oral administration showed no difference between enantiomers, indicating no stereo-selectivity in the passive diffusion process. (R)-Methadone bioavailability ranged from 66.8 to 100%.

The volume of distribution of methadone is large, with average values ranging from 4 to 6.7 L/kg. With a single dose, (R)methadone has a lower protein binding and therefore has a larger volume of distribution than -methadone In Opoid users receiving long-term oral methadone, the mean distribution half-life has been reported to be 5.8 h. Values for terminal half-life indicate differences between the 2 enantiomers and between healthy subjects and Opoid addicts. (R)-Methadone has a longer terminal half-life, average 37 h (range 30.5 g) compared to 28 h range for -methadone.

The racemate terminal half-life ranges from 13 to 60 h. Healthy subjects who had never taken methadone had a shorter terminal half-life than Opoid patients at the beginning of treatment, who in turn had a shorter terminal half-life than Opoid patients at steady state. Mean oral clearance in healthy subjects and Opoid patients showed the same trend regarding the difference between enantiomers in healthy subjects and Opoid patients.

Kristensen et al. found clearance rates of 158 mI/min and 129 mI/min for (R)- and (S)-methadone, respectively, and 96 mL/min for the racemate. Wolff et al. compared healthy subjects with Opoid users and found mean oral clearance rates of 115 mI/min and 53 mI/min, respectively. Following treatment with the same methadone dose, large inter-individual variations of methadone plasma concentrations have been documented.

This variation ranged between 7- and 17-fold. A detectable increase in the plasma concentration occurred within 15 to 30 min. peaking between 1 and 4 h after oral dosing. Peak plasma concentrations after 15 mg, 100-120 mg, and chronic administration of 100- to 200-mg doses were 0.075 mg/L, 0.86 mg/L, and 0.83 mg/L, respectively. The range of peak plasma concentrations seen after high chronic dosing was 0.57 to 1.06 mg/L.

The peak plasma concentration after an IV dose of 10 mg was 0.50 mg/L. The use of methadone IV resulted in a higher concentration to dose ratio of (R)-methadone (23% increase) due to the loss of metabolism in the gut wall and loss of the liver first-pass effect. Large inter-individual variability in the (R) plasma ratio of methadone occurred. Eap et al. found a range of 0.63-2.4 in plasma samples of 22 addicted patients under racemic methadone maintenance treatment and a range of 0.55 to 2.55 (mean 1.14; SD = 0.37) with a larger population of 211.

Methadone is primarily eliminated from the body by metabolism in the liver. A total of 9 metabolites of methadone have been identified. In human urine, Methadone is metabolized to 2 minor pharmacologically active metabolites, methadol and normethadol. The primary metabolic pathway for methadone is by mono- and di-N-demethylation, followed by spontaneous cyclization to form 2-ethylidene-1-5-dimethyl-3,3-diphenylpyrrolidine.

(EDDP) and 2-ethyl-5-methyl-3,3-phenylpyrroline (EMDP). The process of N-demethylation has not been shown to be stereoselective. Methadone, EDDP, and EDMP also undergo hydroxylation in the pars position of one of the phenyl rings and glucuronide conjugation. Methadone is metabolized extensively by the cytochrome P450 enzymes, primarily via CYP3A4, with possible involvement of CYP2C9 and CYP2C19. There are mixed reports in the literature regarding the involvement of iso-enzymes CYP1A2 and CYP2D6, with CYP2D6 preferentially metabolizing (R)-methadone.

Following a single oral dose of methadone, unchanged methadone and EDDP account for up to 50% of the dose. Other identified metabolites contribute quantitatively very little. Methadone may account for 5 to 50% of the dose in 24 h urine specimens of methadone maintenance subjects with EDDP accounting for 3 to 25% of the dose. Since methadone is a weak base, urinary pH has a marked effect on its excretion into urine. Acidifying the urine resulted in an increase in the amount of unchanged methadone excreted, leading to increased drug clearance.

Nilson et al. found excretion percentages of 22% of the prescribed dose in 24 h for acidic conditions compared to only 5% under alkaline conditions. Less effect of urine pH on EDDP excretion was observed. Variations in urine drug concentrations also are effected by urine volume, dose, and rate of metabolism. Patients excrete significantly more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Lesser amounts of EDDP are found in the feces, 6 to 18%, with methadone found at <1% of the dose.

Methadone elimination is significantly more rapid for pregnant patients (half-life 19 h} compared to non-pregnant patients Half-life 30 hr. Pregnancy may also decrease the fraction of methadone absorbed, thus having an impact on the apparent clearance and volume of distribution. Differences in hormone concentrations during the phases of pregnancy could significantly alter the absorption of orally administered drugs, such as methadone.

Less extensive methadone gastrointestinal absorption may also contribute to lower plasma concentrations during pregnancy. Inter-individual variation is too great to correlate urinary excretion concentrations of methadone or EDDP to methadone dose. This relationship does not improve with correcting for creatinine concentration in urine specimens. If a single subject is repeatedly monitored over a period of several days, it may be possible to determine a trend for that individual. However, this requires quantification of every urine specimen and therefore is not practical.

Morphine

Morphine is widely used in the management of moderate to severe paint Multiple preparations are available for the administration of morphine by subcutaneous, IM, IV, epidural, or intrathecal injection. Typical dose ranges are 1-10 mg/kg. Oral preparations are also available in standard release and extended release. Oral dosages range from 20 to 200 mg per day.  Morphine is the archetypical µ-receptor agonist. As such it produces anti-nociceptive response at both the spinal level and brain level.

The side effects are the classic Opoid effects of nausea, dry mouth, miosis, and constipation. Morphine is also usually referred to as a central nervous system depressant. However Opoids also have psycho-stimulant properties independent of any analgesic effects. For morphine, these effects appear to be primarily modulated by stimulation of dopamine release in the nucleus accumbens. The serum half-life for morphine is about 3 h.

A single IM 8.75-mg/70 kg dose resulted in a 0.070 mg/L peak serum concentration 10 to 20 min after dosing. Vainio et al. reported a steady-state blood morphine of 0.066 mg/L in cancer patients receiving 209 mg/day. Westerling et al. reported 0.0071 mg/L serum morphine after a 10-mg IV dose. Because of high first-pass metabolism only 20 to 40% of oral morphine is bioavailable.

Approximately 5% of the dose is N-demethylated to form normorphine that does not appear to have pharmacological activity. The majority of morphine is corrugated to form morphine-3-glucuronide that then undergoes biliary excretion. Up to 87% of a morphine dose is excreted in the urine, with 75% present as morphine-3-glucuronide. In vivo, M6G is much more active than morphine itself, with an ED50 for morphine of 928 ng and 7.3 ng for M6G.

Permeability of M6G may be greater than anticipated because of conformational forms of M6G that minimize polar group exposure. This is contradicted by Wu et al. who reported a 32-fold lower uptake of M6G into the brain than morphine. Miosis, vomiting, unconsciousness, and respiratory depression classically indicate overdose of morphine. Doses greater than 30 mg parenterally or 100 mg orally can be toxic to a naive adult. Doses of 120 mg may be lethal. One individual demonstrated blood concentrations of 0.62, 6.2, and 11 mg/L of morphine, morphine-3-glucuronide, and M6G 60 h after a 5-g dose of extended-release tablets. Overdose responds well to supportive treatment and administration of naloxone.

Oxycodone

Oxycodone, 14-hydroxy-7,8-dihydrocodeinone is a semi-synthetic narcotic analgesic derived from thebaine. Given subcutaneously, oxycodone is approximately equipotent to morphine and is prescribed for the relief of pain that requires treatment for more than a few days. Available for clinical use since 1915 oxycodone is marketed in many tablet, capsule, and liquid formulations, which contain from 2.25 to 5.0 mg of oxycodone. Many of these formulations also contain aspirin, phenacetin, or caffeine.

From 1990 to 1996 oxycodone’s therapeutic use increased by 23%. During the same time periods the reports of abuse decreased by 29% and the estimated number of emergency department episodes were stable. In 1996 a controlled-release preparation marketed as OxyContin was made available in 10 mg, 20 mg, 40 mg, 80 mg, and strength. OxyContin tablets are taken every 12 h. This product has been the focus of drug abuse on the East Coast, as it is reported to give a high very close to that of heroin. OxyContin abusers will chew the tablets, crush the tablets and snort the powder, or dissolve the oxycodone in water and Infect the liquid for the maximum effect. Oxycodone abuse has been a problem since the 1960s, but now a steady increase in Oxy addicts in methadone programs has been seen. The numbers of emergency department episodes involving oxycodone have dramatically increased since the release of OxyContin in 1996. With IV administration the relief of pain is immediate, within 5 to 8 min. and lasts for approximately 4 h. Assuming that complete absorption after IM administration has taken place, oral oxycodone has a bioavailability of 60%.

This is a higher oral bioavailability than morphine and is believed to be because of the 3-methoxy substitution that prevents extensive first-pass glucuronidation. Time to Cmax ranges from 1 to 1.5 h. Mandema et al.  demonstrated that the absorption profile of the controlled-release oxycodone tablets begins with a rapid absorption component (t1/2= 37 mins) that accounts for 38% of the available dose. This is followed by a slow absorption phase at (T1/2 = 6.2 h) that accounts for the remaining 62% of the dose. Two 10-mg tablets of oral controlled-release oxycodone hydrochloride were found to be 102.7% bio-available relative to 20 mg of immediate-release oxycodone hydrochloride oral solution. The controlled-release tablets allow an effective plasma concentration of oxycodone to be reached Tricky and for this effective concentration to be maintained for a longer period of time than with immediate release oxycodone, allowing for dosing every 12 h. Unlike immediate release formulations, controlled-release oxycodone was also shown to be bioequivalent under fed and fasted conditions. Rectal administration, with a mean bioavailability of 61%, results in a delayed relief of pain, 0.5 to 1.0 h, but also provides a longer duration of analgesia ranging from 8 to 12 h. Oxycodone can also be administered intra-nasally where it is rapidly and effectively absorbed from the nasal mucosa The mean bioavailability has been shown to be 46%, but had wide variation, limiting its clinical usefulness. Mean elimination half-life ranges from 2 to 5.5 h, with marked inter-individual variation.

Plasma concentrations following a single oral dose of 4.5 mg reached a peak of 0.009 to 0.037 mg/L. Imposing with 20 mg controlled-release oxycodone resulted in a mean Cmax of 0.0186 mg/L at 2.62 h, while dosing with 20 mg of immediate-release oxycodone resulted in a mean Cmax of 0.0416 mg/L at 1.30 h. A similar Cmax of 0.0204 mg/L ,0.0232 mg/L and 0.0201 mg/L after a dose of 20 mg controlled-release oxycodone were reported respectively by Heiskanen et al., Kaiko et aL, and Benziger et al. Using an IM dose of 0.14 mg/kg oxycodone hydrochloride, Poyhia et al. reported a Cmaxof 0.034 mg/L and a Cmax of 0.038 mg/L for a 0.28 mg/kg oral dose. Oxycodone is metabolized in the liver through N- and O demethylation, 6-ketoreduction, and corrugation with glucuronic acid. The O-demethylation reaction is catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6) with the end product of oxymorphone, an analgesic that has a potency approximately 10 times that of morphine.

The resulting plasma concentration of oxymorphone is very low in comparison to that of oxycodone; therefore, oxymorphone is not responsible for the analgesic effect of a dose of oxycodone, if demethylation results in noroxycodone that has only weak affinity for the µ-Opoid receptor. If the action of CYP2D6 is blocked, the concentration of noroxycodone increases as oxymorphone decreases (80; Veto reduction results in the formation of 6-oxycodol. About 8 to 14% of the dose of oxycodone is excreted in the urine as un-conjugated and corrugated oxycodone over a 24-h period. Oxymorphone is excreted mainly as a conjugate; noroxycodone is found mostly in un-conjugated form. Noroxycodone concentrations in plasma and urine were found to be higher after oral administration when compared to IM administration.

The pharmacokinetics of oxycodone and noroxycodone showed no significant differences among young men, young women elderly men, and elderly women. Differences in the pharmacokinetic profile of oxymorphone were observed among these 4 groups.

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