Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Tuesday, February 14, 2012

Opioid Dependence: About

Physiological Tolerance & Dependence 

Homeostatic balance and cyclic AMP induced upregulation:

For a regular opioid agonist such as morphine, subjective effects (including analgesia), for all practical purposes, are dose dependent. More specifically, the agonist effect at opioid receptors which underlies these effects is concentration dependent. As the concentration of opioid in the blood increases, more receptors become occupied, thus increasing the net value of narcotic effect.

Over a period of time with consistent use, a level of tolerance begins to develop for a number of pharmacological effects; namely euphoria, analgesia, nausea, sedation, and respiratory depression. Receptors become desensitized and begin requiring higher blood concentrations of opioid in order to respond.

As opioid use continues, neurons adapt at the cellular level to the inhibition produced through the opioid receptors. They adapt with a compensatory mechanism of increasing neuro-excitatory potential - so that if opioid induced inhibition were to discontinue, vigorous firing of the excited cell would ensue - i.e post-synaptic cells will more easily respond to neurotransmitter reception coming from pre synaptic sites; or presynaptic cells may be more inclined to release excitatory transmitters into their synapse. This compensation is mediated by upregulation of a chemical known as cyclic AMP, and serves as a prototypic model for the process of homeostatic balance (i.e. homeostasis): multiple contrasting mechanisms in the body competing (in this case inhibition vs excitation) in order to maintain a balanced middle ground. If the inhibitory mechanism (i.e. opioid receptor stimulation) were to cease in the heat of this competitive process, the opposing excitatory mechanism would quickly dominate, being unhindered to work at full power, so to speak. Think of it as two people arm wrestling each other - both are working their muscles at full power, but if one is to suddenly give up in the middle of the game, the opponents current strength will cause the quitters arm to fold onto the table.

Pharmacological tolerance and weakened endogenous opioid system:

Meanwhile, once significant tolerance has developed, the body's natural opioid system - essential in modulating sensitivity to pain and emotional affective states - has adapted to the presence of narcotics by producing less of its own. The endogenous (i.e. natural) opioids which are available are no longer sufficient to satisfy opioid receptors, which have become desensitized with the consistent use of powerful exogenous narcotics. This being further excacerbated by the current state of cyclic AMP upregulation and neuronal excitation.

Under the aforementioned circumstances, if narcotic use is to become interrupted in a dependent individual, leading opioid-blood concentration to fall below the needed level; the now opioid tolerant central nervous system throws a fit. With no inhibitive stimulation to satisfy receptors, much less to simply compensate the ever increasing neuroexcitatory potential, the pathways of the CNS fire begin firing, receiving, and transducing stimuli vigourously, functioning to an extent far above pre-dependence levels. The now upregulated autonomic nervous system has more power than usual to work with, but with less opioid than normal to work with. It is now unhindered and left to respond with a dysregulated state of complete excitation - i.e. sympathomemesis or hyperarousal. This manifests as the acute withdrawal syndrome: panic & anxiety, agitation, tension, spasms, sensitivity to pain & touch, and a raw state of general pain & discomfort, these are mediated in large part by the hypothalamic pituitary adrenal axis (HPA) - to include the locus coeruleus (LC), an area of the brainstem rich in norepinephrine neurons which, when inhibited, plays a key role in the calming & anxiolytic effects of opioid agonists.

Opioid Withdrawal: A Syndrome of Autonomic Imbalance:

A majority of the physiological symptoms in opioid withdrawal are mediated by the aforementioned state of autonomic imbalance - Characterized by excitation (over-firing of neurons) in areas of the midbrain and brainstem, to include the HPA axis. In terms of symptoms, this manifests asl; insomnia, thermal dysregulation (fever or chills & gooseflesh), hypertension & tachycardia, mydriasis (dilated pupils), hyper-arousal of the sympathetic system (anxiety, panic, muscle spasms, sweating), anorexia, nausea and vomiting.

Sensory hypersensitivity or hyperalgesia often occurs due to excitation at the dorsal horn of the spinal cord.

Dysregulation of cholinergic neurons in the GI tract results in diarrhea and bowel discomfort.

Due to their action on limbic structures involved in the emotional perception of pain, opioid withdrawal is often accompanied by depression or emotional hypersensitivity, whether or not a subject is psychologically dependent on opioids.

In cases of severe psychological dependence (see below), limbic dysregulation and emotional stress often serves to precipitate or potentiate the physiological symptoms of withdrawal; taking an otherwise moderate flu-like experience and producing some terrible discomfort. - this is known as a psychosomatic response.

Psychodependence: A Syndrome of Learned Reinforced Behavior

This term is used to describe a phenomenon in which a drug user becomes psychologically and emotionally dependent on opioids; typically after a period of regular use. This form of dependence often contributes to a behavioral pattern of drug seeking and habitual drug use (in this case, narcotics).

For the sake of convenience, lets refer to this phenomenon variably as habituation or addiction.

The biological mechanism underlying addiction to opioids is but one of multiple components contributing to what is predominantly a behavioral phenomenon of opioid habituation; It is important to not that the biological components to addiction discussed herein serve as an associative, influential or predispositional factor rather than a causative factor. After all, humans are not robots devoid of intelligence and free will.

Use of an opioid agonist results in 2 psychological responses:

1) the subjective perception of the opioid itself and its CNS/physiological effects. These effects are mediated by the mu1 receptors in the midbrain as well as mu2 receptors throughout the spinal cord.

2) a mu-1 mediated increase in dopaminergic firing throughout the limbic structures of the brain; also known as the pleasure centers or reward, reinforcement & learning pathways. Note: dopaminergic activity in the limbic regions not only mediates reinforcement and learning, but exhibits a blunting effect on the emotional perception of pain.


The result of #2 is largely dependent on one's subjective perception of the narcotic effects. Reinforcement can be positive or negative, depending on whether one perceives the effects of a drug as pleasurable, aversive, or perhaps neutral. The users' perception of the drug (1) dictates whether he is taught through reinforcement (2) to seek the drug, or to avoid the drug, in the future.

When one finds the experience aversive, there is typically no point in repeating the experience again - with the exception of treating pain - and no desire to repeat the experience again.

When one finds the effects particularly pleasant, the associated positive reinforcement can lead to a desire for repeating the experience, whether it be right away or at another time - as you can already see, the phenomenon that is known as "addiction" is simply driven by biochemical changes in the brain; so many factors in this process are completely subjective to ones own decision making and ones own behavior. This is exactly the problem with pathologizing such a phenomenon.

When the latter subject repeatedly uses the drug, his limbic system continues to reinforce this behavior positively, eventually teaching him to continue repeating the experience. Such drug use is a LEARNED behavior, in the same way that evolutionary behaviors are learned - sex and reproduction, the struggle for food, water, or shelter. Drug use is not the only non-evolutionary behavior learned & reinforced through this process; other hedonistic behaviors are learned this way as well, including but not limited to masturbation, comfort-eating, gambling, excercizing, socializing, falling in love, kissing, shopping, skydiving.

Continued use of the drug (or continuation of such other aforementioned hedonistic behaviors), not to mention all environmental & sensory stimuli which have become associated with the use of this drug (including and perhaps especially, its pharmacological effects), over time become wired into the instinctual or evolutionary drive. This here is the biological component referred to when addiction, or the popular "addicted brain" scans, are spoken about. These behaviors become prioritized, and desired, behaviors - while the unique personal manner in which an individual responds to this phenomenon being completely subjective, distinct.

The important distinction between behavior and biology:

The neurobiological component of addiction can make it very difficult to change such behaviors, even if they've become self-destructive. After all, they've been prioritized. However as I have emphasized and will continue to emphasize, this is not to say that the dependent subject has no control over this behavior - he does. Opioid addicts (or those addicted to other drugs) have every bit as much control over their drug-desires as they do over their sexual desires. Our human civility, motivation, and intelligence (all of which by the way have just as much neurobiological basis as our cravings or instincts) are the forces which restrain us, keep us from acting on primitive sexual or survival impulses and other animalistic behaviors, not to mention our hedonistic drive.

It is very important to note; opioids do not inevitably cause pleasure. A major portion of those who try or take opioids for any purpose find the effects boring or undesireable. Most individuals report opioids simply making them drowsy or nauseated.

Meanwhile, as I stated earlier, drug induced reinforcement can be positive or negative. The pharmacological effects produced by a drug are but one of many sensory/environmental/experiential factors with which our limbic brain associates with the behavior of drug taking. If one can understand this concept, one will understand the important distinction between behavior and biological disposition; that which distinguishes drug related brain changes with the act itself of seeking, obtaining, and using drugs, all which in modern discourse have been wrongfully classified as inexorable from brain chemistry. Schaler makes a great analogy with alcoholism & chronic smoking - drinking is a behavior, while cirrhosis of the liver is a disease; smoking is a behavior, while lung cancer is a disease. Drinking is not cirrhosis and smoking is not lung cancer. Unless we're ready to consider the pathological desire for drugs itself to be a disease, we cannot accurately classify opioid dependence as an illness.

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