Drugs of misuse act at local cellular and membrane sites that are within a neurochemical system that is called the Reward and Withdrawal Pathway (11). This pathway is in the meso-limbic dopamine system, and it involves, among other structures, the ventral tegmental area, nucleus accumbens, amygdala, and prefrontal cortex of the primitive brain. Addiction is a neurobiological disease that causes disruption of this pathway. This disruption is mediated via receptor sites and neurotransmitters. Central to this reward and withdrawal pathway is the neurotransmitter dopamine, which has been shown to be relevant not only to drug reward, but also to food, drink, sex, and social reward (12,13). Disruption of this neurochemical pathway by drugs of abuse may lead to addiction. Drug withdrawal can intensify with repeated drug use and can persist during prolonged periods of drug abstinence, a symptom complex known as the protracted abstinence syndrome (14). This sensitization of a neural process related to drug cravings, or to environmental stimuli associated with drugs (referred to as cues), leads, in the at risk individual, to the progressive increase in drug-seeking behavior that characterizes addiction. Such sensitization appears to increase the attractiveness of the drug taking and that of the drug-associated stimuli (15). Addiction is a treatable brain disease; it is a distinct medical condition that may or may not be associated with the patient's pain syndrome (16,17).
Physical dependence, conversely, is a natural expected physiologic response that can occur with opioids, alcohol, benzodiazepines, corticosteroids, antidepressants, diabetic agents, certain cardiac medications, and many other medications used in clinical medicine. Abrupt cessation or rapid dose reduction resulting in decreasing blood level of the substance and/ or administration of an antagonist to the substance can produce a withdrawal syndrome that can include, but is not limited to, nausea, vomiting, diaphoresis, diarrhea, abdominal cramps, seizures, or even death (15).
Opioids cause physical dependence and, upon abrupt discontinuation, withdrawal as a result of upregulation of the cyclic aminophosphorase pathway at the locus coeruleus (14). This is a normal physiologic response to this class of medications. It should be noted that most of the medications mentioned above are capable of producing physical dependence, but are not associated with the disease of addiction. A heroin addict may be both addicted and physically dependent on the narcotic, while the pain patient taking opioids is physically dependent, but not addicted. Both will experience withdrawal if the drug is abruptly stopped.
Tolerance is also a natural, expected physiologic response that can occur with exposure to certain classes of drugs, especially alcohol and opioids. Pharmacodynamic tolerance involves adaptations that occur at both the site of the drug action; e.g., receptor, ion channel, and in related systems more distal to the site of the drug action. For example, pharmacody-namic tolerance to opioids is evident at both the level of the opioid receptor in the locus coeruleus (primary) and in the dopaminergic reward pathways afferent to the site of this discrete drug action (secondary) (15). Both persons addicted to heroin and chronic pain patients taking opioids can exhibit tolerance to certain effects of the drug.
The terms ''pseudotolerance'' and "pseudoaddiction" are very important in pain management. Pseudotolerance, as defined by Pappagallo, is the need to increase medication such as opioids for pain, when other factor(s) are present but unappreciated as disease progression, new disease, increased physical activity, lack of compliance, change in medication, drug interaction, addiction, and/or deviant behavior (18).
The American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine [Liaison Committee on Pain and Addiction (LCPA) approved the following definitions in 2001] (19).
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