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THE DISEASE
Despite
research that continues to point to genetic responsibility for
addictive potential, debate continues over whether psychology or
pharmacology is the major component. Current theories, though,
suggest that psychological problems associated with addiction to
drugs or alcohol are actually symptoms of the underlying
physiological disease and secondary to it. Addiction is seen as a
primary chronic disease with genetic, psychological, and
environmental factors; and addiction is generally recognized as
essentially an obsessive-compulsive disorder independent of any
physiological dependence involved.
Understanding the neurobiological
mechanisms involved requires an integration neurobiology with social
psychology,
experimental
psychology, and psychiatry. Addiction
presents
as a cycle of
progressive dysregulation of brain reward systems
resulting in
compulsive drug use
and loss of
control over drug-taking. Sensitization and counteradaptation
contribute to
this hedonic homeostatic dysregulation;
and
involvement of the mesolimbic
dopamine
system, opioid peptidergic systems, and brain and hormonal
stress systems
continue to unfold.
Source:
G. F. Koob, M.L.
Moal. Drug Abuse: Hedonic Homeostatic Dysregulation. Science.
Volume 278, Number 5335 Issue of 3 Oct 1997, pp. 52 - 58
Opioid Receptors
The analgesic and
addictive properties of opioid drugs as well as normal function of
numerous endogenous mediators are thought to result from their
interaction with neuronal-membrane-bound proteinaceous delta, kappa,
and mu opioid receptors. These three major classes of opioid
receptors have a variety of subclasses; and various compounds react
with these receptors in different intensities and in different ways,
with opioid drugs producing not only the euphoria and analgesia
associated with their use and abuse, but the constipation, urinary
retention, sedation, respiratory depression, nausea, and confusion as
well.
Endogenous substances like the neuropeptides (endorphins,
enkaphalins, dynophins) interacting with the receptors both in the
CNS and elsewhere in the body can elicit responses as diverse as
analgesia to suppression of protein synthesis, schizophrenia, and
immune response regulation.
It is
clear that such substances act not only on receptors in specific
parts of the brain, but on similar receptors in other organs and
tissues. Recent evidence supports this theory, showing a direct
correlation between opioid withdrawal and changes in the
hypothalamic-pituitary-adrenal (HPA) axis, which not only precede
clinical and adrenergic symptoms but persist after they subside as a
response to naloxone therapy. In fact, cortisol levels –
neuroendocrine changes in the HPA axis – are seen as a more
accurate indicator of withdrawal than adrenergic symptoms.
Thus,
therapeutic application of opioid medications can have profound and
as yet unpredictable effects on a host of biological processes beyond
pain relief that cannot be ignored. Specifically, morphine has been
found to exert an inhibitory effect on immune responses, presumably
by competing with inflammatory mediators.
This information helps to
explain the analgesic benefits observed with acupuncture, direct
electrical stimulation of parts of the brain and spinal cord, and
hypnosis, which probably enhance release, production, and/or activity
of endogenous neuropeptides. Further, an individual’s clinical
response to any given stimulus to selective activation, inhibition,
or interaction among these receptors is under genetic control,
leading to speculation that the tendency to become addicted may also
be genetic.
Sources:
Press
release - The therapeutic effects of morphine:
http://www.cnrs.fr/English/Compresse/kieffer240698.htm
PP
Presentation: vhttp://www.nyssa-pg.org/HANYS/auth/ahcpr/tsld019.htm
Kaufman,
et al.
The analgesic and addictive properties of morphine and other opioid
drugs. Journal
of Biological Chemistry, 1995, 270(26):15877-83.
J.
Culpepper-Morgan, M. Kreek. Hypothalamic-Pituitary-Adrenal
Axis Hypersensitivity to Naloxone in Opioid Dependence: A Case of
Naloxone-Induced Withdrawal.
Metabolism
46(2):130-134, 1997.
Raynor
K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T
Pharmacological characterization of the cloned kappa-, delta-, and
mu-opioid receptors. Molecular
Pharmacology 45 : 330-334 (1994).
HEROIN
An alarming increase in
the rate of addiction to heroin has been observed over the last five
years, especially among the middle class whose previous drug of
choice was cocaine. Contributing factors to the increase among teens
and young adults include the following:
* Involvement of young
healthy people (who present with fewer medical and legal
complications) in heroin use and sale looms large. When perceived
consequences are minimal, peer pressure takes a greater toll.
People with money and time to spend are more likely to be influenced
by affluent, healthy drug-using peers than by derelict junkies
sleeping in dumpsters.
* Ready availability of
very pure heroin makes abuse by snorting and smoking viable as
routes of administration, avoiding or delaying more invasive IV use
and the stigma associated with that more drastic route that was
necessary when street supplies were less potent. In times past, IV
administration was necessary to produce the desired effects with
opiate content of 5 or 10% in street heroin; but today’s street
supplies typically contain 15 to 20% of active opiate, fully capable
of delivering a high via other routes. Without the potential of
blood-borne diseases associated with IV use, more people are willing
to experiment with the drug.
Methadone
remains by far the predominant treatment choice, as it has for almost
30 years. While detoxification of a heroin addiction with morphine
usually requires 4 or 5 doses per day, methadone’s long duration of
action facilitates maintenance with only a single daily dose. In a
stable patient, a single daily dose of methadone successfully blocks
the euphoric effects of shorter-acting heroin for up to 36 hours,
thus reducing the tendency to use street drugs.
Outcome
is closely correlated with dose, with patients receiving less than
50mg per day experiencing 5 times the relapse rate of those getting
more; and optimal dose seems to be between 65 and 75mg per day for
most patients. Doses below 60mg per day are inappropriate. In spite
of the fact that higher doses consistently produce more favorable
outcomes, though, a variety of factors tend to favor lower doses,
some treatment programs having policies that prohibit prescription of
doses in excess of 30mg per day
* Lower doses produce
fewer side effects.
* Lower doses
facilitate less diversion to street markets.
* Methadone maintenance
is not a cure, and abstinence is still believed a viable option by
some clinicians.
* Patients may also
resist higher doses, falling prey to the preconceptions that higher
doses decrease libido, “rot the bones,” and that methadone
addiction is even more difficult to recover from than heroin
addiction.
Though
heroin is not hepatotoxic, liver damage is the most common serious
ailment among addicts; and that complicates treatment with
methadone, especially in severe liver dysfunction. Pregnancy
typically reduces the bioavailability of methadone, presumably by
enhanced hepatic metabolism; so dosage must be titrated to clinical
response.
Drug
interactions are also a major source of dosage complications, since
those who seek treatment for addiction typically suffer varied
comorbid states or persist in abuse of other drugs while on methadone
therapy.
Alcohol
can be a major issue, since methadone patients frequently abuse
alcohol during therapy. Short-term high alcohol intake inhibits
methadone metabolism, while chronic high intake potentiates
metabolism. Low levels of blood alcohol following high levels can
also accelerate metabolism of methadone. Since other options for
concurrent treatment of alcoholism in the methadone patient
(naltrexone and naloxone) would precipitate withdrawal symptoms,
disulfuram is the only remaining option. It is commonly used with
success, but it impairs the n-demethylation of methadone and thus can
impair elimination.
It
has been suggested that methadone therapy can actually increase the
desire to abuse cocaine, since opioids tend to potentiate or prolong
cocaine euphoria and assuage the dysphoria. When methadone doses are
increased (to over 100mg per day) in response to cocaine use, though,
cocaine use tends to decrease. It seems that cocaine use with higher
doses of methadone actually precipitate opiate withdrawal symptoms
and increase cocaine dysphoria by adrenergic stimulation. Rapid
changes in opioid blood levels can enhance cocaine euphoria, so use
of LAAM (see section below on LAAM), with its longer duration of
action and steadier blood levels may help assuage cocaine use; and
buprenorphine, with its reduced opioid-agonist activity might also
prove a valuable substitute in such cases.
Tuberculosis
is not uncommon among such populations, and rifampin enhances the
hepatic metabolism of methadone, often precipitating withdrawal
symptoms.
Since
IV drug use is commonly associated with HIV and AIDS, antiviral
agents may warrant extra attention. Protease inhibitors can inhibit
methadone metabolism by inhibiting the cytochorome P450 enzymes
systems, while AZT toxicity has been observed for unknown reasons in
patients taking methadone.
Seizure
disorders, too, are not uncommon; and hydantoins, carbamazepine, and
barbiturates all enhance methadone metabolism via potentiation of
hepatic enzymes to precipitate withdrawal symptoms.
Cimetidine
not only inhibits cytochrome P450 enzyme systems, but it reduces
blood flow to the liver, impairing hepatic metabolism of methadone.
This may be considered a viable tactic to reduce methadone dosage in
some cases, but patients should be warned of this potential with the
ready non-prescription availability of cimetidine.
Source:
S. Stine, T.
Kosten. Methadone Dose in the Treatment of Opiate Dependence.
Medscape Mental Health.
http://www.medscape.com/Medscape/MentalHealth/1997/v02.n11/mh3076.stine/mh3076.stine.html.
New Light On Some Old Products That Can Be Used
Instead Of Methadone
Levomethadyl
acetate hydrochloride (LAAM), BioDevelopment’s Orlam™, was
approved in 1993 for treatment of narcotic addiction but has never
reached the popularity of methadone with treatment programs.
Originally touted as “similar to methadone in its capacity to
discourage heroin use and block withdrawal symptoms,” its
advantageous three-day-per-week administration seems to have failed
to gain acceptance among addicts. Lack of efficacy in providing the
necessary opiate-like effects early in treatment left users without
the feeling that it was working – prompting them to drop out of
treatment programs.
A recent study reported in Archives
of General Psychiatry(August, 1998), though,
indicates that with proper dosing and on the proper schedule, it is
as effective and acceptable to recipients as methadone. It seems
that a common problem with prior efforts at utilization, patients
were titrated upward slowly – too slowly to be effective. Acting
on the same mu opioid receptors as heroin and methadone, LAAM
occupies the receptors for longer periods of time to block activity
of other opiates, preventing both withdrawal as well as rewarding
effects. Efforts are underway to determine an optimal starting dose
for LAAM, as its longer duration of action makes it both more
compliance-friendly and potentially less expensive than methadone.
Buprenorphine (available from Reckitt &
Colman in 1ml amps 0.324mg/ml as Buprenex™), has also been used
successfully for opioid withdrawal in sublingual tablet form (for
which a New Drug Application has been filed). As a mixed opioid
agonist-antagonist, it is approved for analgesia and bears less abuse
potential than morphine with comparable analgesic efficacy. Though
some abuse has been reported, laboratory analysis of its reward and
aversion properties confirms its lower potential for abuse than the
opiates. Clinical studies comparing it to methadone for opioid
withdrawal show similar initial efficacy; but in spite of its
once-daily dosage that provides no compliance advantage over
methadone, buprenorphine proved superior in producing consistent
improvement in opioid-positive urines over time.
Patient
accounts laud buprenorphine as a savior. Having tried methadone with
minimal success because it causes its own high and seems almost as
addictive as heroin for many, most patients experience only a brief
high and no perpetuation of the physiological dependence. Another
study at Johns Hopkins, though, showed that heroin addicts maintained
on buprenorphine experience withdrawal on both naloxone and
naltrexone, confirming that maintenance on the agent does produce
physical dependence.
Sources:
E.
Strain, M. Stitzer, I. Liebson, G. Bigelow.
Buprenorphine
Versus Methadone in the Treatment of Opioid Dependence:
Self-Reports, Urinalysis, and Addiction Severity Index.
Journal
of Clinical Psychopharmacology 16(1):58-67, 1996
J. Cloud. A Way
Out For Junkies. Time Jan. 19, 1998, Vol
151, No 2.
M. Gaiardi, M.
Bartoletti, A. Bacchi, C. Gubellini, M. Babbini. Motivational
properties of buprenorphine as assessed by place and taste
conditioning in rats. Psychopharmacology
Vol. 130 Issue 2 (1997) pp 104-108.
Eissenberg et al., Assessment of
Buprenorphine's Physical Dependence Potential
Journal of Pharmacology and
Experimental Therapeutics, 276, pp. 449-459, 1996.
Public Policy
Statement on Buprenorphine. American Society of Addiction Medicine.
http://207.201.181.5/ppol/buph.htm.
Rapid Detox for Heroin Addicts
Ultra-Rapid
Opiate Detoxification (UROD) is a process of detoxifying opiate
addicts under general anesthesia within four-to-seven hours with
naltrexone, thus avoiding the weeks of miserable symptoms of the
acute phase of withdrawal. Patients are generally hospitalized for
48 to 72 hours, then released on a regimen that generally includes
naltrexone, counseling, and perhaps support groups and twelve-step
assistance. Also known as Rapid Anesthesia-Assisted Detoxification
(RAAD), and pioneered in Europe over ten years ago, the program is
now widely accepted and administered by a number of specialty
treatment centers around the country using variations on that name,
all boasting a 100% success rate.
The first long-term study of the
process, reported October 4, 1998 before a convention of the American
Psychiatric Association, followed 120 patients for six months and
found that 55% remained drug-free after that time. This contrasts
sharply with the 10-20% success rate of other methods of
detoxification at a cost usually below $10,000.
Source:
Doctor’s
Guide To The Internet: http://www.pslgroup.com/dg/B2EFA.htm.
Here are some contacts:
NEURAAD, with facilities all
over the country: http://www.neuraad.com/contact.htm
The
Center for Narcotics Detoxification Under Anesthesia:
http://www.detox911.com/contact.html (or
1-888-DETOX-911)
The UniQual Network:
http://www.uniqual.com/ (or 508-620-5916)
The National Detox Center of St.
Louis: http://www.nationaldetox.com/ (or 888-480-8008)
FOLLOW-UP ON MEDICAL THC
Dronabinol,
Unimed Pharmaceuticals, Inc.’s Marinol™ is indicated for
treatment of nausea and vomiting associated with cancer chemotherapy
in patients not responding adequately to conventional antiemetic
treatment and treatment of appetite loss in people with HIV. As the
only legally-available synthetic form of THC, concern over addictive
or abuse potential has persisted; but results of a recent study
presented College of Problems of Drug Dependency's annual scientific
meeting confirms that no cases of abuse have been observed among
patients. The nation-wide nine-month study entailed analysis of
experience of researchers, physicians, addiction medicine
specialists, and law enforcement agencies to arrive at the following
conclusions:
* Dosages tend to remain within
therapeutic ranges, even with long-term use.
* Since the product fails to elicit effects
considered desirable in a drug of abuse, Cannabis-dependent
populations have demonstrated no interest in it.
* There seems to be no street
market for dronabinol and no evidence of diversion for sale as a
street drug.
Source:
Doctor’s Guide To The
Internet: http://www.pslgroup.com/dg/872E6.htm
GABA
Gamma-aminobutyric
acid (GABA) acts as an essential inhibitory transmitter in the
central nervous system (See September’s PowerGraph
on its role in epilepsy and its metabolism). While GABA exerts its
inhibitory effects in the brain, glycine sees to play that role in
the brain stem; and enhancement of the activity of both entities by
receptor stimulation seems to be involved in producing the CNS
depression and unconsciousness observed with both general anesthetics
and alcohol.
Not only do the findings provide a
valuable stepping stone toward designing safer and more effective
anesthetics and antagonists, it is speculated that it may provide
insight into alcoholism and addiction. Finding precise and
differential sites of action could help explain why some people seem
to have a genetic tendency toward alcoholism and addiction while
others do not. It could also provide a basis for designing
medications and gene therapy to treat addictions.
Sources:
Nature,
September 24, 1997
Ingrid
Wickelgren, Teacing the Brain to Take Drugs.
Science. Volume 280, Number 5372 Issue
of 26 Jun 1998, pp. 2045 – 2047.
AN APPROVED ALTERNATIVE TO PHARMACOTHERAPY FOR
ADDICTION
Needle
acupuncture treatment has received the official sanction of the
National Institutes of Health (NIH), as a twelve-member panel issued
its statement recommending the treatment for a variety of symptoms
including nausea and vomiting, post-operative dental pain, addiction,
stroke rehabilitation, headache, menstrual cramps, tennis elbow,
fibromyalgia, low back pain, carpal tunnel syndrome, and asthma. One
of the oldest and most common therapeutic modalities of traditional
medicine, the science has been practiced for at least 2,500 years and
revolves around the theory that patterns of energy flow called Qi
(pronounced "chee") throughout the body are essential for
optimal health and can be modified by acupuncture.
The panel encourages extensive
clinical study to “integrate the theory of Chinese medicine into
the conventional Western biomedical research model and into the
conventional health care arena," since “acceptance of
acupuncture as a reliable therapeutic choice in Western medicine will
depend on such rigorous studies.” They also emphasize the need for
more careful regulation and qualification of practitioners,
especially non-physician practitioners. Though professional
licensure is required by most states, standardization of licensure
requirements in encouraged to provide uniform standards and protect
the public.
Source:
NIH website --
http://odp.od.nih.gov/consensus/cons/107/107_statement.pdf
