Opiates are a type of compounds that occur naturally in opium that is present in the poppy plant, known as Papaver somniferum. These compounds include morphine and codeine. Codeine is usually commercially made from morphine, however. Synthetic or semi synthetic opiates are actually opioids, but are rarely referred to by that name. Commonly prescribed synthetic opiates include buprenorphine, butorphanol, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, and oxymorphone.
Medicinal Use and Abuse
Heroin (or diacetylmorphine} is the most commonly abused opiate, and has been for a long time. The incidence of heroin use has risen and fallen over time based on its availability. At one time it was thought to be most frequently abused in poor, inner-city neighborhoods of large urban areas where it was most accessible, but today heroin abuse is widespread and crosses all socioeconomic lines. It is a Schedule I substance that is not available by prescription, making its use strictly illegal. Some synthetic opiates, particularly hydromorphone and oxycodone, are also widely abused. However, DHHS guidelines and DOT regulations currently limit drug testing to codeine and morphine, although non-federal testing may include other related opiates.
Morphine was first isolated from crude opium in 1803. It is a Schedule II substance and is available by prescription for use in treatment of moderate to severe pain. It is most commonly used to treat postoperative pain and pain associated with cancer. Morphine is usually administered par-enterally, although it may be given orally.
Codeine, first isolated from opium in 1832, is a much weaker analgesic than morphine and by itself is prescribed for mild to moderate pain. Codeine is frequently prescribed in medications that contain other ingredients including acetylsalicylic acid, acetaminophen, butalbital, carisoprodol, and promethazine. Because codeine is also an effective anti-tussive, it is available in various cough and cold medications, as well. Codeine is usually a Schedule III drug, although in some anti-tussive preparations it is a Schedule V drug. In those preparations, a pharmacist record of purchaser instead of a prescription may be evidence of legal use.
The principal effects of opiate intoxication include miosis, respiratory depression, analgesia, sedation, ptosis, and confusion. Moderate motor stimulation may occur depending on the size of a dose and period between doses. Subjective effects include euphoria, relaxation, and energization. Physical dependence, in addition to tolerance, occurs with opiate abuse.
Metabolism and Analytical issues
Codeine is excreted as free codeine (5-17%), corrugated codeine (32-46%), conjugated norcodeine (0-21%), and corrugated morphine (5-13%). Low amounts of free norcodeine and morphine may also be detected. Norcodeine, free and conjugated morphine, and codeine are found in urine for up to 4 days after use. Initially there is more codeine than morphine, however after time, morphine concentrations may exceed codeine.
Heroin has a plasma half-life of about 2 min and is rapidly metabolized to 6-acetylmorphine (6-AM) and morphine. 6-AM can only be detected at low concentrations for up to 8 h in the urine. Despite the short time window for detecting 6-AM after heroin use, its presence is conclusive evidence for heroin use. For that reason, DHHS guidelines and DOT regulations require the laboratory to test for and report the result of a 6-AM test on all cordoned morphine-positive test results. By far, the predominant metabolite identified after heroin use is morphine.
In patients receiving morphine, initially 25 to 34% of the total amount of morphine present in the urine was free morphine, but this ratio declined after 12 h to an average of only 5.94% of total morphine. Generally, less than 10% of morphine is excreted as free morphine, with the remainder excreted in the urine as conjugates, primarily as morphine 3-glucuronide with lesser amounts as morphine-3-glucuronide. Morphine does not metabolize to codeine. Detection times for both codeine and morphine in urine average 1 to 3 days.
Because morphine is usually detected in the urine after use of morphine, codeine, or heroin, it is difficult to determine the source of a morphine-positive test result without further information. The pathways of heroin, morphine, and codeine metabolism are illustrated in Figure 1.1. While the GC-MS confirmation assay distinguishes morphine and codeine, it does not definitely identify the source of the metabolite. In addition to the difficulty of determining whether a positive morphine result was due to codeine, morphine, or heroin use, the interpretation of an opiate positive result is further complicated because the ingestion of poppy seeds can result in urinary morphine or codeine concentrations that exceed the DHHS/DOT drug-testing cutoff concentrations.
A review of several early studies that compared the concentrations of morphine and codeine in urine after the ingestion of poppy seeds, concluded that morphine concentrations exceeding 5,000 ng/mL were indicative of heroin, morphine, or codeine use and that a morphine-to-codeine ratio of less than 2 was indicative of codeine use and would rule out popper seed ingestion. However, in another study in which 5 subjects ate 2 Danish pastries, each containing 12 g of poppy seeds, the average maximum urinary morphine and codeine concentrations were 11,571 and 4861 ng/rnl, respectively. That study also showed that positive results could be obtained up to 72 h after the ingestion of streusel containing 24 g of poppy seeds.
The authors concluded that while most findings support the guideline that morphine concentrations exceeding 5,000 ng/mL in urine are indicative of heroin, codeine, or morphine use, 13% of the specimens collected within 24 h after poppy seed streusel ingestion had morphine concentrations exceeding 5,000 ng/mL In addition, many of these specimens contained codeine in concentrations that exceeded the 300 ng/mL cutoff that was required at the time by DHHS Guidelines and DOT. All studies were in agreement in that no specimen had a morphine-to-codeine ratio of less than 2 due to the ingestion of poppy seeds. There are no published studies of poppy seed ingestion where the urine morphine concentration exceeded 11,600 ng/mL or the codeine concentration exceeded 2,800 ng/mL.
Because of the many possibilities that could explain a positive opiate test result, federal regulations state that before the MRO verifies a confirmed positive result for opiates, where the morphine or codeine concentration is less than 15,000 ng/mL, he/she shall determine that there is clinical evidence, in addition to the urine test d-amphetamine, of unauthorized use of any opium, opiate, or opium derivatives. Clinical evidence includes recent needle tracks, behavioral and psychological signs of acute opiate intoxication or withdrawal, clinical history of unauthorized use recent enough to have produced the laboratory test result, or use of medication from a foreign country.
Admission of taking a prescription medicine that has been prescribed for someone other than the donor is also considered ‘clinical evidence’ of abuse. Clinical evidence of unauthorized opiate use is not required for verifying a morphine- or codeine-positive result of 15,000 ng/mL or greater. In those instances, the donor must provide proof of legitimate medical use of morphine or codeine. Additionally, DHHS guidelines consider a level of codeine and/or morphine greater than 15,000 ng/mL to be ‘Clinical evidence’ of abuse if the donor is unable to provide a prescription for the opiate in his or her name.
Clinical signs of abuse are not required if the urine contains 6 AM. DHHS guidelines and DOT regulations require that certified laboratories report CAM concentrations at a 10 ng/mL cutoff. One study found that CAM could be detected in over 50% of the specimens that contained morphine at concentrations exceeding 5,000 ng/mL. However, this study was conducted on samples from probationers, in whom the incidence of heroin use is bluely to be higher than in the general population.
Occasionally, an individual will volunteer the information that he or she took medication prescribed for someone else, frequently a spouse. This is particularly common with medications containing codeine. Current MRO practices suggest that the MRO declare these cases to be verified positives, since such use is not medically authorized. However, the DOT regulations require that if the individual did not tell the MRO that he or she took another person’s prescription medication, the MRO must, lacking clinical evidence of unauthorized use discussed above, determine that the test is negative. Thus, many MROs who are working under DOT testing guidelines feel obligated at the beginning of the interview to inform individual with an opiate-positive urinalysis that admission of use of another’s medication will be treated as a verified positive. For the many reasons indicated above, most of the confirmed opiate-positive test results reported to the MRO is reported as negative to the employer.