Understanding the Sources of Morphine
Morphine is a popular narcotic analgesic that is derived from the opium poppy, Papaver somniferum. It has a history of use dating back 2,000 years, but was first chemically isolated in 1806. Currently, morphine is used medicinally worldwide for moderate to severe pain in acute and chronic pain management.1,2 Because of its popularity and high potential for abuse, it is strongly suggested that morphine be monitored during patient use.
When morphine is detected in urine, a clinician’s next step is determining its origin. One challenge with morphine is that it has various sources. Four recognized sources of morphine are codeine, heroin, morphine, and poppy seed ingestion. These sources can cause confusion and misinterpretation in pain management. It is incumbent on the clinician to ask questions that may provide insight into possible sources. Examples of such questions include:
- Does the patient have a history of heroin abuse?
- Does the patient have a prescription for codeine or morphine from another provider?
- Has the patient recently consumed a codeine-containing product such as cough syrup?
- Has the patient recently consumed a food containing poppy seeds?
In some cases, further evaluation, such as testing for codeine or 6-monoacetylmorphine (6-MAM), the metabolite of heroin, may be needed to determine the source. Since the presence of morphine can result from expected sources, such as a prescription for morphine or abuse of prescription or illicit drugs, it is imperative that clinicians understand the various sources of morphine in order to better elucidate the origin of morphine detected in urine drug monitoring.
Pharmacology and Toxicology
Morphine has relative selectivity for the µ opioid receptor, although at higher doses it has been shown to have interaction with the κ and δ opioid receptors.3,4 Detection of morphine on a urine drug test provides information that morphine or a substance that metabolizes or contains morphine has been ingested in the preceding 2 to 4 days (Table 1).
If morphine is prescribed, the expected urine drug test result should demonstrate the presence of morphine (Figure 1). In some circumstances, a small amount of hydromorphone or codeine may be detected. Hydromorphone is a minor metabolite of morphine and may be detected in the urine after consumption of high doses of morphine.5-7 Codeine, if detected in low amounts, may be present as a contaminant from the manufacturing process. While the presence of hydromorphone and/or codeine is not necessarily expected routinely, it is possible in the context of a patient receiving a prescription for morphine.
Codeine is a prodrug, and is metabolized to morphine through cytochrome P450 2D6 (CYP2D6).5 In individuals who have consumed codeine, the expected urine drug test result should demonstrate the presence of codeine and morphine (Figure 2). It has been suggested that evaluating the codeine to morphine ratio may provide insight into whether codeine is the sole source of morphine present in the urine specimen; if the codeine to morphine ratio is <6, there is likely an additional source of morphine.7 However, it is important to recognize that if a patient is taking a codeine medication as needed and it has been a day or two after a dose, it is possible that only morphine may be detected. Additionally, a patient’s CYP2D6 genotype or concomitant use of CYP2D6 enzyme inhibitors may impact codeine to morphine ratios in urine by impacting codeine metabolism, thereby limiting the utility of this ratio when trying to determine the source of morphine.
Heroin (diacetylmorphine) is rapidly metabolized from diacetylmorphine to 6-MAM, which is subsequently metabolized to morphine.5 Diacetylmorphine and 6-MAM have very short half-lives, making detection difficult. If an individual has used heroin, the expected urine drug test result would demonstrate the presence of morphine, and possibly 6-MAM (Figure 3). The only source of 6-MAM is heroin; thus, if 6-MAM is detected, it is concluded that the individual has recently ingested heroin.8,9 The detection time of 6-MAM in the urine is approximately 8 hours following heroin use.9 If only morphine is present, it is difficult to determine whether heroin has been consumed, though the presence of large quantities of morphine may be an indicator of heroin consumption. A small study of heroin users found urine morphine levels ranging from 1,400 to 87,350 ng/mL, with half of the individuals having a urine morphine level above 8,000 ng/mL.10 In another study of 63 heroin users, the mean urine morphine level was 62,370 ng/mL (range 7,100 to 476,000 ng/mL), and 80% of the participants had morphine levels >15,000 ng/mL.11 However, a high level of morphine cannot definitively indicate abuse of heroin in the absence of 6-MAM, as high levels of morphine may also result from morphine or codeine use or abuse.
Ingestion of poppy seeds can produce positive morphine results on a urine drug test. The amount of morphine present is often less than 2,000 ng/mL following poppy seed consumption,12 although it is possible for higher concentrations to be present. It has been suggested that urine samples can be analyzed for the presence of thebaine as a marker of poppy seed ingestion.13 This has not been widely adopted in clinical practice. If low levels of morphine are present, a detailed patient history may aid in determining whether poppy seeds have been consumed recently, and are contributing to the positive drug test result. Figure 4 provides an example of a low level of morphine detected, possibly resulting from consumption of poppy seeds as no prescription for morphine or codeine was reported for this individual.
There are four commonly recognized sources of morphine: codeine, heroin, morphine, and poppy seeds. When trying to determine the source of the morphine found on a urine drug test, a clinician may look for additional information present on the laboratory report, such as presence of codeine or 6-MAM. If one of these compounds is detected, the source of morphine may be narrowed down. If neither of these compounds is detected, it is difficult to determine the source of morphine without additional information from the patient history and clinical presentation.