Drug Tolerance

When talking about drug tolerance, you’re talking about “a decline in effects following repeated use.” Consequently, more and more must be consumed, in order to achieve the same intensity of effect. Heroin tolerance is no different. Over time, more and more heroin must be used to achieve the desired effect.

In the very beginning, many heroin addicts will spend about $20.00 a day to get high all day. A year later and it may be $100.00 per day to get high all day. This change is the result of heroin tolerance. Incidentally, many of the behavior changes that you see with heroin addiction, i.e. not eating, not socializing, criminality (prostitution, shoplifting, etc…) are linked in some way to the phenomenon of heroin tolerance.

Definitions

  • Heroin Tolerance is a state of adaptation, caused by chronic exposure to a heroin, that induces changes that result in a reduction of effects over time.
  • Heroin dependence is a state of adaption, whereby a person is now susceptible to opioid withdrawal syndrome following any prolonged attempt at cessation.
  • Heroin Addiction, a.k.a. psychological dependence to heroin, is a chronic illness characterized by heroin craving, compulsive heroin use, and impaired control over intake.

 

Heroin effects

Narcotics like heroin, are typically consumed in high doses. Consequently, they produce multiple effects, such as pain relief, euphoria, respiratory depression, sedation, pinpoint pupils and more. We know that some of heroin’s effects develop tolerance quickly, others not so quickly, and a few effects never develop tolerance at all.
 

Progression of heroin tolerance

Heroin’s euphoric effect, develops tolerance significantly quicker than respiratory depression. Consequently, as heroin addicts increase the dosage in order to keep getting high, they run an ever increasing risk of overdosing. Even so, the vast majority of heroin overdoses are the result of poly-substance abuse, such as mixing heroin with alcohol, benzodiazepines or other narcotics such such as fentanyl or oxycodone.

One of heroin’s more innocuous drug effects is constricted pupils, esoterically known as “being pinned.” This particular drug effect never develops tolerance. That’s why medical professionals check for it whenever they suspect someone is overdosing.
 

Rate of heroin tolerance

Timeline

  • Euphoria  –  quick rate of tolerance
  • Sedation  –  quick rate of tolerance
  • Nausea  –  moderate rate of tolerance
  • Respiratory depression  – moderate rate of tolerance
  • Itchiness  –  slow rate of tolerance
  • Constipation/Urine retention  –  no tolerance
  • Pupil constriction  –  no tolerance

 

Understanding heroin tolerance

Tolerance to drugs can be produced in different ways, but with heroin, tolerance typically develops at the cellular level and currently, there are two accepted theories related to the development of heroin tolerance. Neither theory diminishes the validity of the other. Therefore, both theories may be true.

  • One theory suggests that prolonged heroin use desensitizes opioid receptors, which means the receptors do not signal normally and thus produce less drug effects. We know now that desensitization of all classical opioid receptors occurs by phosphorylation. Now that sounds complicated and to be truthful it is, but phosphorylation just means adding of a phosphate group, which in turn changes how the receptor functions.

 

  • The second theory is opioid receptor down-regulation, which traditionally refers to a reduced number of functional receptors present in the cell. It occurs via internalization of the opioid receptors from the cell membrane. The cell membrane closes around the opioid receptor, effectively creating a bubble of cell membrane around the receptor and drawing it into the body of the cell. Once inside the intracellular environment, the opioid receptor can no longer function and is effectively down-regulated.

 

Cross tolerance:

Cross-tolerance to opioids refers to the property of tolerance that has developed following chronic exposure to one opioid that generalizes to a second opioid. If the extent of tolerance to the second opioid drug is similar to the original opioid then cross-tolerance is symmetric, if not it is asymmetric.
 
 
 
 

Innate and acquired heroin tolerance

There are two basic subtypes of heroin tolerance, “innate” and “acquired.” Innate heroin tolerance is the biological make-up of the user, which refers to the genetic predisposition of the individual to exhibit sensitivity or insensitivity to heroin from the initial dose. In contrast, acquired heroin tolerance is a consequence of repeated exposure to heroin, which can be subdivided into three general categories: learned, pharmacodynamics and pharmacokinetic.

Learned, Pharmacodynamics and Pharmacokinetics

1) Learned heroin tolerance is a type of placebo effect. If you believe drugs lose effectiveness over time than drugs will lose effectiveness over time. But it goes even further. If a heroin addict repeatedly injects heroin in a similar environment like in the bathroom. The bathroom itself manifests certain signals or heroin tolerance re-stimulators. The sink, tile floor or sitting on a commode or listening to the fan all become tolerance re-stimulators and each re-stimulator helps negate heroin’s overall effect.

We know now that longtime heroin users display increased tolerance to heroin in locations where they repeatedly use. If a heroin user injects in a non-familiar location, this environment-conditioned tolerance (learned heroin tolerance) does not occur, which results in a greater drug effect.

If a heroin addict typically injects heroin in the bathroom, but decides to inject heroin outside on a park bench, where heroin tolerance re-stimulators are less prevalent, the heroin user is much more likely to overdose. The heroin user’s typical dose, in the face of decreased tolerance, becomes far too high and can become deadly. Many experts believe that learned heroin tolerance (environment-conditioned tolerance) and location change are believed to be responsible for numerous heroin fatalities each year.

The phenomenon of learned tolerance can work in reverse too. If a heroin addict is sick from heroin withdrawal and sees the dealers’ car he or she experiences withdrawal relief albeit temporary. One of the unusual observations is that drug craving is most intense while waiting to acquire heroin and that drug cravings subside once heroin is acquired. Most heroin addicts can relate to this form of learned response as it happens every single day.

 

2) Pharmacodynamic heroin tolerance is represented by a decrease in heroin effects over time, pertaining to diminished responsivity of the opioid receptor system caused by repeated heroin use.

 

3)  Pharmacokinetic heroin tolerance refers to changes in the metabolism of a heroin user after repeated administration that may inhibit release of certain enzymes, active moiety or hormones.

 

a) Enzyme

An enzyme is a protein molecule that acts as a biological catalyst with three characteristics. First, the basic function of an enzyme is to increase the rate of a reaction. Most cellular reactions occur about a million times faster than they would in the absence of an enzyme. Second, most enzymes act specifically with only one reactant (called a substrate) to produce products. The third and most remarkable characteristic is that enzymes are regulated from a state of low activity to high activity and vice versa. Gradually, you will appreciate that the individuality of a living cell is due in large part to the unique set of some 3,000 enzymes that the body is genetically programmed to produce. If even one enzyme is missing or defective, the results can be disastrous.

 

b) Active moiety

The part of a drug that makes the drug work the way it does.

 

c) Hormone

Hormones are chemical substances that act like messenger molecules in the body. After being made in one part of the body, they travel to other parts of the body where they help control how cells and organs do their work.

Related to heroin tolerance

Heroin stimulates the brain and spinal cord to dampen down pain signals. While that is a primary effect, there is a small paradoxical effect, even from the initial dose, that actually results in pain amplification. The more heroin you use, the more sensitive you become to pain.

Chronic heroin use that leads to greater pain sensitivity is known as hyperalgesia. The development of heroin-induced-hyperalgesia can best be described as driving your car with one foot on the brake and one foot on the gas. The more heroin you use (gas) the more sensitive you become to pain (brakes). The problem seems to be that chronic heroin use, i.e. the stepping on the gas, facilitates the transmission of pain signals (brakes), which makes more heroin necessary to get the desired effect.

There is work being done in opioid therapies for heroin addiction and looking at the pain threshold of people who are on methadone maintenance. As compared with controls, methadone maintenance patients are clearly hyperalgesic (greater pain sensitivity) and have a much lower threshold for pain.
 

Conclusions:

Two different but somewhat similar effects occur with chronic heroin use. First, opioid receptors become less effective over time. Second, less and less opioid receptors are available to be activated. Most scientific evidence suggests that both decreased receptor activation and receptor down-regulation are responsible for heroin tolerance.
 

Frequently Asked Questions

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Heroin and Memory Loss

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