Fentanyl is a
synthetic primary μ agonist opioid, currently the
most widely used synthetic opioid analgesic
worldwide, with a primary potency approximately 81
times that of morphine.[1] Fentanyl has an LD50 of
3.1 milligrams per kilogram in rats, 0.03 milligrams
per kilogram in monkeys, and an as of yet
undetermined LD50 in humans; however, analgesic
doses start at 10μg/IV in an opioid-naive
individual. Dozens of fentanyl analogs have been
developed, the first being Janssen Pharmaceutica's
Sufentanil which entered clinical practice as a
general anaesthetic under the trade name Sublimaze
in the early 1960's. Additionally, Fentanyl is
classified as a Schedule II drug in the United
States due to its potential for abuse, comparable to
other cross-tolerant opioids such as morphine.
Analogues
The pharmaceutical industry has developed several
analogues of fentanyl:
Alfentanil (trade name Alfenta), an ultra-short
acting (5–10 minutes) analgesic.
Sufentanil (trade name Sufenta), a potent analgesic
(5 to 10 times more potent than fentanyl) for use in
heart surgery.
Remifentanil (trade name Ultiva), currently the
shortest acting opioid, has the benefit of rapid
offset, even after prolonged infusions.
Carfentanil (trade name Wildnil) is an analogue of
fentanyl with an analgesic potency 10,000 times that
of morphine and is used in veterinary practice to
immobilize certain large animals such as elephants.
A number of other fentanyl analogues exist which are
classified in the USA as Schedule I drugs, meaning
that they have "no currently accepted medical
use".[2] Many of these drugs have been sold on the
street as "China White".[3] These drugs include:
Methylfentanyl (thought to be
the active constituent of Kolokol-1, a chemical
weapon)
Methylthiofentanyl
Acetyl-α-methylfentanyl
methylfentanyl (see below)
methylthiofentanyl
hydroxy-3-methylfentanyl
hydroxyfentanyl
flurorofentanyl
Thiofentanyl[4]
Adverse events
Fentanyl's major side effects (more than 10% of
patients) include diarrhea, nausea, constipation,
dry mouth, somnolence, confusion, asthenia
(weakness), and sweating and, less frequently (3 to
10% of patients), abdominal pain, headache, fatigue,
anorexia and weight loss, dizziness, nervousness,
hallucinations, anxiety, depression, flu-like
symptoms, dyspepsia (indigestion), dyspnea
(shortness of breath), hypoventilation, apnea, and
urinary retention. Fentanyl use has also been
associated with aphasia.[7] Fentanyl patch has been
associated with altered mental state leading to
aggression in an anecdotal case report.[8]
Adverse effects
Like other lipid-soluble drugs, the pharmacodynamics
of fentanyl are poorly understood. The manufacturers
acknowledge there is no data on the pharmacodynamics
of fentanyl in elderly, cachectic or debilitated
patients, frequently the type of patient for which
transdermal fentanyl is being used. This may explain
the increasing number of reports of respiratory
depression events since the late
1970s.[9][10][11][12][13][14][15] In 2006 the U.S.
Food and Drug Administration started investigating
several respiratory deaths, but doctors in the UK
had to wait until September 2008 before being warned
of the risks with fentanyl.[16]
The precise reason for sudden respiratory depression
is unclear, but there are several hypotheses:
Saturation of the body fat compartment in patients
with rapid and profound body fat loss (patients with
cancer, cardiac or infection-induced cachexia can
lose 80% of their body fat).
Early carbon dioxide retention causing cutaneous
vasodilatation (releasing more fentanyl), together
with acidosis which reduces protein binding of
fentanyl (releasing yet more fentanyl).
Reduced sedation, losing a useful early warning sign
of opioid toxicity, and resulting in levels closer
to respiratory depressant levels. Fentanyl has a
therapeutic index of 270.[17]
Illicit use
Fentanyl powder seized by a Lake County Deputy
Sheriff in Painesville, Ohio, where a male subject
had been discovered unresponsive and struggling to
breatheIllicit use of pharmaceutical fentanyls first
appeared in the mid-1970s in the medical community
and continues in the present. United States
authorities classify fentanyl as a narcotic. To
date, over 12 different analogues of fentanyl have
been produced clandestinely and identified in the
U.S. drug traffic. The biological effects of the
fentanyls are similar to those of heroin, with the
exception that many users report a noticeably less
euphoric 'high' associated with the drug and
stronger sedative and analgesic effects. Because the
effects of fentanyl last for only a very short time,
it is even more addictive than heroin, and regular
users may become addicted very quickly.
Additionally, fentanyl may be hundreds of times more
potent than street heroin, and tends to produce
significantly worse respiratory depression, making
it somewhat more dangerous than heroin to users —
though in some places, it is sold as heroin, often
leading to overdoses. Fentanyl is most commonly used
orally, but like heroin, can also be smoked, snorted
or injected. Many fentanyl overdoses are initially
classified as heroin overdoses.[18]
Fentanyl is normally sold on the black market in the
form of transdermal fentanyl patches such as
Duragesic, diverted from legitimate medical
supplies. The patches may be cut up and eaten, or
the gel from inside the patch smoked. To prevent the
removal of the fentanyl base, Janssen-Cilag, the
inventor of the Fentanyl patch, designed the
Durogesic patch. The Durogesic patches contain their
Fentanyl throughout the plastic matrix instead of
gel incorporated into a reservoir on the patch.
Manufacturers such as Mylan have also produced
Durogesic-style fentanyl patches that contain the
chemical in a silicone matrix, preventing the
removal of the fentanyl-containing gel present in
other products.[1] Another dosage form of fentanyl
that has appeared on the streets is fentanyl
lollipops Actiq, which are sold under the street
name of "percopop". The pharmacy retail price ranges
from US$10 to US$30 per unit (based on strength of
lozenge), with the black market cost anywhere from
US$15 to US$40 per unit, depending on the strength.
Non-medical use of fentanyl by individuals without
opiate tolerance can be very dangerous and has
resulted in numerous deaths.[2] Even those with
opiate tolerances are at high risk for overdoses.
Once the fentanyl is in the user's system it is
extremely difficult to stop its course because of
the nature of absorption. Illicitly synthesized
fentanyl powder has also appeared on the US market.
Because of the extremely high strength of pure
fentanyl powder, it is very difficult to dilute
appropriately, and often the resulting mixture may
be far too strong and consequently very dangerous.
Some heroin dealers mix fentanyl powder with larger
amounts of heroin in order to increase potency or
compensate for low-quality heroin, and to increase
the volume of their product. As of December 2006, a
mix of fentanyl and either cocaine or heroin has
caused an outbreak in overdose deaths in the United
States, heavily concentrated in the cities of
Detroit, Philadelphia, Pittsburgh, St. Louis,
Milwaukee, Camden, Chicago,[19] Little Rock, and
Dallas.[20] The mixture of fentanyl and heroin is
known as "magic" or "the bomb", among other names,
on the street.[21]
Several large quantities of illicitly produced
fentanyl have been seized by U.S. law enforcement
agencies. In June 2006, 945 grams of 83% pure
fentanyl powder was seized by Border Patrol agents
in California from a vehicle which had entered from
Mexico.[22] Mexico is the source of much of the
illicit fentanyl for sale in the U.S. However, there
has been one domestic fentanyl lab discovered by law
enforcement, in April 2006 in Azusa, California. The
lab was a source of counterfeit 80-mg OxyContin
tablets containing fentanyl instead of oxycodone, as
well as bulk fentanyl and other drugs.[23][24]
The "China White" form of fentanyl refers to any of
a number of clandestinely produced analogues,
especially α-methylfentanyl (AMF)[25][26], which
today are classified as Schedule I drugs in the
United States.[27] Part of the motivation for AMF is
that despite the extra difficulty from a synthetic
standpoint, the resultant drug is relatively more
resistant to metabolic degradation. This results in
a drug with an increased duration.[28]
Overdoses, recalls, and legal action
This section does not cite any references or
sources. Please help improve this article by adding
citations to reliable sources. Unverifiable material
may be challenged and removed. (April 2009)
A number of fatal fentanyl overdoses have been
directly tied to the drug over the past several
years. In particular, manufacturers of time-release
fentanyl patches have come under scrutiny for
defective products. While the fentanyl contained in
the patches was safe, a malfunction of the patches
caused an excessive amount of fentanyl to leak and
to be absorbed by patients, resulting in
life-threatening side effects and even death.
External
links
-
Description of use of Fentanyl in Russia as an incapacitating weapon. See also Moscow theater hostage crisis
-
Fentanyl: Emergency Response Database. National Institute for Occupational Safety and Health.