Opiate analgesics are some of the oldest and most common medications in clinical practice, but have also been abused since at least 300 b.c. Nepenthe (Greek “free from sorrow”) helped the hero of the Odyssey, but widespread opium smoking in China and the Near East has caused harm for centuries. Since the first chemical isolation of opium and codeine 200 years ago, a wide range of synthetic opioids have been developed, and endogenous opioid peptides were discovered in 1995. Two of the most important adverse effects of all these agents are overdose and dependence. The 0.14% annual prevalence of heroin dependence in the United States is only about one-third the rate of prescription opiate abuse and is substantially lower than the 2% rate of morphine dependence in Southeast and Southwest Asia. While these rates are low relative to other abused substances, their disease burden is substantial, with high rates of morbidity and mortality; disease transmission; increased health care, crime, and law enforcement costs; and less tangible costs of family distress and lost productivity.
The diagnosis of opiate dependence in the Fourth Diagnostic and Statistical Manual (DSM-IV) requires the repeated use of the drug while producing problems in three or more areas in a 12-month period. The areas include tolerance, withdrawal, use of greater amounts of opiates than intended, and use despite adverse consequences. The abuse diagnosis is related to legal problems, inability to meet obligations, use in hazardous situations, and continued use despite problems. The most striking aspect of opiate abuse has been its marked increase as the gateway to illicit drugs in the United States. Since 2007, prescription opiates have surpassed marijuana as the most common illicit drug that adolescents initially abuse.
The most commonly abused opiates are diverted prescriptions for oxycodone, followed by heroin and morphine, and—among health professionals—meperidine and fentanyl. Two opiate maintenance treatment agents—methadone and buprenorphine—are also abused, but at substantially lower rates, and the partial opiate agonists such as butorphanol, tramadol, and pentazocine are infrequently abused. The chemistry and general pharmacology of these agents are covered in major pharmacology texts, and this chapter focuses on the neurobiology and pharmacology relevant to abuse, dependence, and their treatments.
During the past 30 years, substantial progress has been made in elucidating the neurobiology of opiates and their effects not only on the three types of opiate receptors (mu, kappa, and delta) but also on the cascade of second, third, and fourth intracellular messenger systems and on neuronal action potentials. The different functional activities of these three receptors are summarized in Table 393-1, and abuse liability is primarily associated with the mu receptor. A fourth type of opiate receptor, the orphanin receptor, also modulates pain but is not affected by opiate drugs. These opiate receptors are all G protein–linked and coupled to the cyclic adenosine monophosphate (cyclic AMP) second messenger system and to potassium channels. Opiates are inhibitory and block the potassium channels from opening and depolarizing the neuron, which would produce an action potential. Thus, opiates acutely inhibit neuronal activity. Analgesia and sedation are induced through this inhibition of specific brain pathways, while the “high” from opiates involves an indirect activation of a different brain pathway—the mesolimbic dopamine pathway.
Table 393-1 Actions of Opioid Receptors
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Table 393-1 Actions of Opioid Receptors
|Mu (μ) (e.g., morphine)||Analgesia, reinforcement euphoria, cough and appetite suppression, decreased respirations, decreased GI motility, sedation, hormone changes, dopamine and acetylcholine release|
|Kappa (κ) (e.g., butorphanol)||Dysphoria, decreased GI motility, decreased appetite, decreased respiration, psychotic symptoms, sedation, diuresis, analgesia|
|Delta (Δ) (e.g., etorphine)||Hormone changes, appetite suppression, dopamine release|
The various effects of opiates are related to the specific neuroanatomic locations of mu receptors. Reinforcing and euphoric effects of opiates occur in the dopaminegic pathway from the ventral tegmental area (VTA) to the nucleus accumbens, where opiates increase synaptic levels of dopamine. This increase is due to inhibition of GABAergic neurons that inhibit both the VTA and nucleus accumbens activity. However, the “high” only occurs when the rate of change in dopamine is fast. Large, rapidly administered doses of opiates block GABA inhibition and produce a burst of nucleus accumbens activity that is associated with “high” in all abused drugs. Therefore, routes of administration that slowly increase opiate blood and brain levels, such as oral and transdermal routes, are effective for analgesia and sedation but do not produce an opiate “high” that follows smoking and intravenous routes. Other acute effects such as analgesia and respiratory depression leading to overdose are due to stimulation of opiate receptors located in other areas such as the locus coeruleus.
Opiate dependence and withdrawal are chronic effects related to the cyclic AMP system. This second messenger phosphorylates various intracellular proteins and produces a cascade of changes reaching into the nucleus and DNA. Immediate early gene products such as c-fos and c-jun are activated followed by regulation of other genes with more sustained protein transcription such as delta c-fos. With these sustained gene activations, several receptor-level changes occur, including downregulation of receptor numbers, reduced neuronal cell-surface receptor trafficking, uncoupling of G proteins from the mu opiate receptors, and upregulation of cyclic AMP second messenger systems. These effects are also reflective of genetic risk factors for drug dependence, with estimates of up to 50% of the risk for dependence due to polygenic inheritance. Specific functional genetic polymorphisms in the mu opiate receptor gene appear associated with this risk for opiate abuse, including one producing a threefold increase in this receptor's affinity for opiates and the endogenous ligand beta endorphin. Epigenetic methylation changes also occur on the DNA of the mu receptor gene of opiate addicts. DNA methylation inhibits gene transcription.
This molecular cascade links acute intoxication and sedation to chronic opiate dependence and ...