Dependence Liability Of Opioids Pharmacological Principles Of Addiction

Dependence or addictive liability (how addictive a drug is likely to be) depends upon how quickly the drug enters/leaves the brain. Also, it is directly proportional to the analgesic potency and it depends on the opioid receptor sites with which the ligand interacts. For instance, members of mixed agonist/antagonists (i.e. nalbuphine, pentazocine, butorphanbol) demonstrate a predominant interaction with the K-opioid receptor, which is characterized by a low dependence liability (Figure II-51). In addition, development of dependence also is related to the speed

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Hydromorphone Hydrocodone Phennperi dine

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Pipadone Levnrphanol Phenazoc in

Peth id ine Pi ri t ramide Pentazoc ine

Figure II-50. Comparable potency of different opioids to induce an antitussive action at equianalgesic doses

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Levorphanol Phenazocine Piminodine

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Na lorphine Pentazocine Nalhuph ine

Figure 11-51. Difference in dependence liability of commonly used opioids of dissociation, i.e how fast the ligand leaves the binding site. For instance, an opioid like buprenorphine is characterized by a low dissociation constant reflecting long binding to the receptor, a long duration of action and a slow separation from the receptor. The definition of addiction is based in two different terms:

1. Physiological dependence produced by repeated drug-taking that is characterized by a withdrawal syndrome, when drug is removed (e.g. alcohol, opiates).

2. Psychological dependence produced by repeated drug taking that is characterized by obsessions and compulsive drug-seeking behaviors; results in a detrimental impairment in physical, mental or social functioning.

There are five classes of abused psychoactive drugs

1. Opioids produce a dream-like state; effects include: analgesic (reduction in pain), hypnotic (sleep inducing), euphoria (sense of happiness or ecstasy) using morphine, heroin, or the cough suppressant codeine.

2. Depressants produce feelings of relaxation/sedation and a dream-like state, anxiolytic (anxiety-reducing) and hypnotic effects; reduce central nervous system activity. Members of the class are alcohol, barbiturates, and benzodiazepines.

3. Stimulants increase alertness, arousal, and elevated mood; activate central nervous system (sympathomimetic = mimic the activation of the sympathetic

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Levorphanol Phenazocine Piminodine

Dextromuramide Pethidine Isnmethadana


Na lorphine Pentazocine Nalhuph ine

Figure 11-51. Difference in dependence liability of commonly used opioids nervous system). Members of this class are cocaine, amphetamines, nicotine, caffeine.

4. Psychedelics produce distortions of perception and an altered sense of reality. Typical representatives are LSD, psilocybine, mescaline, MDMA (ecstasy), and PCP (phencyclidine).

5. Marijuana with one of its major active ingredient THC produces feelings of well-being and sense of acuity (sharpness). It also can produce feelings of relaxation.

Also, it is recognized, that opioids, which demonstrate a fast onset of action or due to their galenical preparation (injection, smoking) result in an immediate high plasma concentration, followed by an instantaneous receptor binding, results in a "kick" with an euphoric feeling. Such preparations therefore are more prone to induce a behavior pattern of abuse. Therefore addictive liability or how addictive a drug is likely to be, depends upon how quickly the drug enters/leaves the brain (Table II-10).

Most importantly, the tendency of opioids to result in an abuse is very much linked to the fact of why and when the opioid is ingested. For instance, an opioid taken only for the mere pleasure will rapidly result in the development of dependency. Contrarily, if an opioid is taken for the attenuation of pain, the likelihood to develop an abuse behavior is very low.

Aberrant drug related behavior has to be suggested when the following signs of abuse are obvious: in physical examination. A routine physical examination can elucidate common complications of heroin use or assist in diagnosing opioid dependence. Chronic intravenous use can be confirmed by the presence of "track" marks, which are callouses that follow the course of a subcutaneous vein. These are caused by repeated injections into adjacent sites over an accessible vein. Tracks are often found in easily accessible body areas, such as the backs of the hands, antecubital fossae, on the legs, or in the neck. Signs of recent injection may be found in unusual places in patients attempting to hide their sites of injection. A thorough examination for tracks or recent injection sites should include looking between the

Table II-10. Factors that influence how quickly a drug will enter the brain

1. Chemical structure: How fatty is the drug (i.e. its lipophilicity)? Does the drug have nutrients that our brain uses?

2. How fast does the drug cross the blood brain barrier (BBB) Lipophilic drugs (i.e. heroin, fentanyl) cross the BBB much faster than hydrophilic agents (i.e., morphine); they mimic nutrients our brain needs and can "slip" through transporters in the BBB.

3. Route of administration: Is the drug entering directly into the blood stream or is it entering first into the stomach? The routes of administration increase the likelihood that a drug enters the blood stream whereby it increases the addictive liability of the drug. Intravenous injection > smoking/snorting > sublingual application > inhalation via nostrils and lungs because they have abundant blood capillaries and more blood supply under the tongue and the lung respectively.

fingers and toes, under the fingernails and toenails, in the axillae, breast veins, and the dorsal vein of the penis.

One complication of drug use that can be found on examination is nasal septal perforation from repeated intranasal insufflation (especially when cocaine is mixed with heroin and snorted). A heart murmur may indicate subacute bacterial endocarditis, a complication of intravenous injection without using good sterile technique. Posterior cervical lymphadenopathy may suggest early viral infection, especially with HIV. Hepatic enlargement may indicate acute hepatitis; a small, hard liver is consistent with chronic viral hepatitis due to hepatitis B or C virus, which are common among injection drug users who share needles.

Signs of opioid intoxication may include pinpoint pupils, drowsiness, slurred speech, and impaired cognition. Signs of acute opioid withdrawal syndrome include watering eyes, runny nose, yawning, muscle twitching, hyperactive bowel sounds, and piloerection. On the other hand the following behaviors are more suggestive of an addiction disorder:

• Selling prescription drugs

• Prescription forgery

• Stealing or "borrowing" drugs from others

• Injecting oral formulations

• Obtaining prescription drugs from nonmedical sources

• Concurrent abuse of alcohol or illicit drugs

• Multiple dose escalations or other non-compliance with therapy despite warnings

• Multiple episodes of prescription "loss"

• Repeatedly seeking prescriptions from other clinicians or from emergency rooms without informing the prescriber or after warnings to desist

• Evidence of deterioration in the ability to function at work, in the family, or socially that appear to be related to drug use

• Repeated resistance to changes in therapy despite clear evidence of adverse physical or psychological effects from the drug

The following behavior pattern is less suggestive of an addiction disorder.

• Aggressive complaining about the need for more drugs.

• Drug hoarding during periods of reduced symptoms.

• Requesting specific drugs.

• Openly acquiring similar drugs from other medical sources.

• Unsanctioned dose escalation or other noncompliance with therapy on one or two occasions.

• Unapproved use of the drug to treat another symptom.

• Reporting psychic effects not intended by the clinician.

• Resistance to a change in therapy associated with "tolerable" adverse effects with expressions of anxiety related to the return of severe symptoms. And while addiction is characterized by a compulsive drug-using and drug-seeking behavior that interferes with normal functioning and causes use of the drug despite increasingly damaging consequences, there are different mechanisms from dependence as addicts can experience intense cravings for drugs even years after sobriety

(after body set-points, etc. should have adjusted back to normal). The nervous pathways involved in the development of dependence is the mesolimbic-dopaminergic reward system, where direct activation (i.e. cocaine, nicotine, alcohol) or inhibition of the inhibitory GABAergic neurons in the ventral tegmental area (VTA) directly project to dopaminergic neurons in the nucleus accumbens (i.e. opioids such as heroin) results in an increased release of dopamine in the nucleus accumbens and stimulation of the prefrontal area resulting in euphoria. On the other hand, insufficient release of dopamine in this area results in dysphoria, which is seen in abstinence (Figure II-52).

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