Opioid Dependence: About

Physiological Tolerance & Dependence 

For a regular opioid agonist such as morphine, subjective effects (including analgesia), for all practical purposes, are dose dependent; however, the agonist effect at opioid receptors which underlies these subjective effects, is concentration dependent. As the concentration of opioid in the blood increases, more receptors become filled, thus increasing the overall 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 increasing blood concentrations of opioid in order to activate.

As opioid use continues, neurons adapt at the cellular level to the inhibition produced by the opioid receptors, through a compensatory mechanism to increase their excitatory potential - so that if opioid inhibition were to discontinue, vigorous firing of the excited cell would ensue. This compensation is mediated by upregulation of a chemical known as cyclic AMP. This is a perfect example of homeostasis: multiple contrasting mechanisms in the body competing (inhibition vs excitation) in order to maintain a balance somewhere in the middle. If the inhibitory mechanism (i.e. opioid receptor stimulation) were to cease in the heat of such competition, the excitatory mechanism would immediately dominate, unleashing all of its power. 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 his arm to fold onto the table.

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 increasing tolerance (not to mention potentiated by an upregulation of cAMP). If narcotic use becomes interrupted in a dependent individual, leading opioid-blood concentration to fall below the required level; the now opioid tolerant central nervous system throws a fucking tantrum - With no inhibitive stimulation to satisfy receptors, not to mention to simply neutralize the ever increasing neuroexcitatory potential, the pathways of the CNS fire signals vigourously, working at a level far above pre-dependence levels. The now upregulated autonomic nervous system has more power than usual to work with; and 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 Locus Coeruleus, an area of the mid-brain that is a key component of the HPA - hypothalamic pituitary adrenal axis.

Opioid Abstinence (i.e. Withdrawal): A Syndrome of Central & Peripheral Dysregulation

A majority of the physiological component in opioid withdrawal is mediated by various symptoms of autonomic dysregulation - Characterized by excitation (over-firing of neurons) in areas of the midbrain and brainstem. These specific symptoms include 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

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 can manifest as a behavioral pattern of habitual narcotic use.

For the sake of convenience, we will refer to psychodependence variably as habituation or addiction.

The biological mechanism underlying addiction to opioids is but one of multiple components contributing to the largely behavioral driven phenomenon of opioid habituation; additionally, the biological component to addiction serves as an associative or predispositional factor rather than a causative factor.

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.

Reinforcement

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 simply next time one has the opportunity.

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, seeking food and water. Drug use is not the only non-essential behavior learned through this process; other hedonistic behaviors are learned this way as well, including but not limited to masturbation, over-eating, gambling, excercizing, socializing, falling in love, shopping.

Continued use of the drug or continuation of these other hedonistic behaviors becomes wired into the instinctual drive with addiction. They become prioritized behaviors, and compulsivity becomes possible. The biological component of addiction can make it very difficult to stop these behaviors, even if they've become self-destructive. After all, they've been prioritized. 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 and intelligence are what keep us from acting on primitive sexual impulses and other violent or animalistic behaviors, as well as our hedonistic desires.

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.