Codeine

Systematic (IUPAC) name

(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol

Identifiers
CAS number 76-57-3
ATC code R05DA04 N02AA59
PubChem CID 5284371
IUPHAR ligand 1673
DrugBank APRD00120
ChemSpider 4447447 
ChEMBL CHEMBL485 
Chemical data
Formula C18H21NO3 
Mol. mass 299.364 g/mol
SMILES eMolecules & PubChem
InChI[show]

Pharmacokinetic data
 Bioavailability ~90% Oral
Hepatic, via CYP2D6 (Cytochrome
Metabolism
P450 2D6)[1]
Half-life 2.5–3 h
Therapeutic considerations
Pregnancy cat.  ?
Controlled (S8) (AU) Schedule I (CA) ?
Legal status
(UK) Schedule II (US)
Dependence liability Low - Moderate
Routes oral, intra-rectally, SC, IM
  (what is this?)  (verify)

Codeine (INN) or 3-methylmorphine (a natural isomer of methylated morphine, the other being
the semi-synthetic 6-methylmorphine) is an opiate used for its analgesic, antitussive, and
antidiarrheal properties. Codeine is the second-most predominant alkaloid in opium, at up to 3
percent; it is much more prevalent in the Iranian poppy (Papaver bractreatum), and codeine is
extracted from this species in some places although the below-mentioned morphine methylation
process is still much more common. It is considered the prototype of the weak to midrange
opioids.

Contents
[hide]

 1 History
 2 Pharmacology
 3 Pharmacokinetics
 4 Indications
 5 Availability
 6 Relation to other opiates
 7 Adverse effects
o 7.1 Withdrawal effects
 8 Recreational use
o 8.1 Detection of use
 9 Controlled substance
o 9.1 North America
 9.1.1 Narcotic content numbers (US & Canada)
 9.1.2 Canada
 9.1.3 United States
o 9.2 Australia
o 9.3 Germany, Switzerland and Austria
 o 9.4 France
o 9.5 Greece
o 9.6 Hong Kong
o 9.7 Ireland
o 9.8 Italy
o 9.9 Japan
o 9.10 Spain
o 9.11 Turkey
o 9.12 United Kingdom
 10 See also
 11 References

[edit] History
Codeine, or O-methylmorphine, is an alkaloid found in the opium poppy, Papaver somniferum
var. album, a plant in the papaveraceae family. Opium poppy has been cultivated and utilized
throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal)
and hypnotic properties linked to the diversity of its active components, which include morphine,
codeine and papaverine.

Codeine is found in concentrations of 0.9 to 3.0 per cent in opium prepared by the latex method
from unripe pods of Papaver somniferum. The name codeine is derived from the Greek word
kodeia for "poppy head." The relative proportion of codeine to morphine, the most common
opium alkaloid at 4 to 23 per cent, tends to be somewhat higher in the poppy straw method of
preparing opium alkaloids.

Until the beginning of the 19th century, raw opium was used in diverse preparations known as
laudanum (see Thomas de Quincey's "Confessions of an English Opium-Eater", 1821) and
paregoric elixirs, a number of which were popular in England since the beginning of the 18th
century; the original preparation seems to have been elaborated in Leiden, the Netherlands
around 1715 by a chemist named Lemort; in 1721 the London Pharmocopeia mentions an Elixir
Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746.

The progressive isolation of opium's several active components opened the path to improved
selectivity and safety of the opiates-based pharmacopeia.

Morphine had been isolated in the early 19th century. Codeine was first isolated in 1832 in
France by Pierre Robiquet, a French chemist and pharmacist already famous for the discovery of
alizarin, the most widespread red dye, while working on refined morphine extraction processes.
This paved the way for the elaboration of a new generation of safer, codeine-based specific
antitussive and antidiarrheal potions.

Codeine is currently the most widely used opiate in the world,[citation needed] and probably the most
commonly used drug overall according to numerous reports by organizations including the
World Health Organization and its League of Nations predecessor agency. It is one of the most
effective orally-administered opioid analgesics and has a wide safety margin. Its strength ranges
from 8 to 12 percent of morphine in most people; differences in metabolism can change this
figure as can other medications, depending on its route of administration.

While codeine can be directly extracted from opium, its original source, most codeine is
synthesized from morphine through the process of O-methylation.[citation needed]

By 1972, the effects of the Nixon War On Drugs had caused across-the-board shortages of illicit
and licit opiates because of a scarcity of natural opium, poppy straw, and other sources of opium
alkaloids, and the geopolitical situation was growing difficult for the United States. After a large
percentage of the opium and morphine in the US National Stockpile of Strategic & Critical
Materials was tapped in order to ease severe shortages of medicinal opiates — the codeine-based
antitussives in particular — in late 1973, researchers were tasked with finding a way to
synthesize codeine and its derivatives. They quickly succeeded using petroleum or coal tar and a
process developed at the United States' National Institutes of Health.[citation needed]

Numerous codeine salts have been prepared since the drug was discovered. The most commonly
used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate
(0.859), and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), and at
least four codeine-based barbiturates, the cyclohexenylethylbarbiturate (0.559),
cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619).
[citation needed]

[edit] Pharmacology
Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds
morphine and codeine-6-glucuronide (C6G).[2][3] Roughly 5-10% of codeine will be converted to
morphine, with the remainder either free, conjugated to form codeine-6-glucuronide (~70%), or
converted to norcodeine (~10%) and hydromorphone (~1%). It is less potent than morphine and
has a correspondingly lower dependence-liability than morphine.[4] Like all opioids, continued
use of codeine induces physical dependence and can be psychologically addictive. However, the
withdrawal symptoms are relatively mild, and, as a consequence, codeine is considerably less
addictive than the other opiates.[clarification needed]

A dose of approximately 200 mg (oral) of codeine must be administered to give analgesia

approximately equivalent to 30 mg (oral) of morphine (Rossi, 2004). However, codeine is, in
general, not used in single doses of greater than 60 mg (and no more than 240 mg in 24 hours).[5]
When analgesia beyond this is required, stronger opioids such as hydrocodone or oxycodone are
favored.

Codeine is metabolized to C6G by uridine diphosphate glucuronosyl transferase UGT2B7, and,

since only about 5% of codeine is metabolized by cytochrome P450 CYP2D6, the current
evidence is that C6G is the primary active compound.[6] Claims about the supposed "ceiling
effect" of codeine doses seemed to rest on the assumption that high doses of codeine saturated
CYP2D6, which prevented further conversion of codeine to morphine, which is simply incorrect.
[citation needed]
There is also no evidence that CYP2D6 inhibition is useful in treating codeine
dependence,[7] though the metabolism of codeine to morphine (and hence further metabolism to
glucuronide morphine conjugates) does have an effect on the abuse potential of codeine.[8]
However, CYP2D6 has been implicated in the toxicity and death of neonates when administered
to lactating mothers, particularly those with increased 2D6 activity ("ultra-rapid" metabolisers).[9]
[10]

[edit] Pharmacokinetics
The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome
P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine,
norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Approximately 6–10% of
the Caucasian population, 2% of Asians, and 1% of Arabs[11] are "poor metabolizers"; they have
little CYP2D6, and codeine is less effective for analgesia in these patients (Rossi, 2004).
Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is responsible for a large
percentage of the analgesia of codeine, and, thus, these patients should experience some
analgesia.[3] Many of the adverse effects will still be experienced in poor metabolizers.
Conversely, 0.5-2% of the population are "extensive metabolizers"; multiple copies of the gene
for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more
quickly than others.

Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion
of codeine to morphine. The most well-known of these are two of the selective serotonin
reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine
diphenhydramine and the antidepressant, buproprion (Wellbutrin, also known as Zyban). Other
drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the
conversion rate.

Since codeine is a prodrug, metabolism differences have the opposite effect. Thus an extensive
metabolizer may have adverse effects from a rapid buildup of codeine metabolites while a poor
metabolizer may get little or no pain relief. CYP2D6 is dysfunctional in 7% of white and black
Americans, resulting in reduced metabolism of codeine. Other individuals may have two or more
copies of the CYP2D6 gene, resulting in rapid metabolism of the target drug. CYP2D6
metabolizes and activates codeine into morphine, which then undergoes glucuronidation. Life-
threatening intoxication, including respiratory depression requiring intubation, can develop over
a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-
rapid metabolism of opioids such as codeine into morphine.[12][13][14]

The active metabolites of codeine, notably morphine, exert their effects by binding to and
activating the μ-opioid receptor.

[edit] Indications
Approved indications for codeine include:
  Cough, though its efficacy in low dose over the counter formulations has been disputed.
[15]

 Diarrhea
 Mild to moderate pain
 Irritable bowel syndrome
 Narcolepsy[16] (Off-label)

Codeine is marketed as both a single-ingredient drug and in combination preparations with the
analgesic acetaminophen (paracetamol), as co-codamol, paracod, panadeine, or the Tylenol With
Codeine series (e.g., Tylenol 3 and 4 tablets and elixir); with the analgesic acetylsalicylic acid
(aspirin), as co-codaprin; or with the NSAID (non-steroidal anti-inflammatory drug) ibuprofen,
as Nurofen Plus. These combinations provide greater pain relief than either agent alone (drug
synergy). Codeine is also commonly marketed in products containing codeine with other pain
killers or muscle relaxers such as Fioricet with Codeine, Soma Compound/Codeine, as well as
codeine mixed with phenacetin (Emprazil With Codeine No. 1, 2, 3, and 4), naproxen,
indomethacin, diclofenac and others as well as more complex mixtures including such mixtures
as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents such as
mentioned above.

Codeine-only products can be obtained with a prescription as a time release tablet (e.g., Codeine
Contin 100 mg and Perduretas 50 mg). Codeine is also marketed in cough syrups with zero to a
half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which
codeine is indicated.

Injectable codeine is available for subcutaneous or intramuscular injection; intravenous injection

can cause a serious reaction that can progress to anaphylaxis. Codeine suppositories are also
marketed in some countries.

[edit] Availability
Codeine phosphate and sulfate are marketed in the United States and Canada. Codeine
hydrochloride is more commonly marketed in continental Europe and other regions, and codeine
hydroiodide and codeine citrate round out the top five most-used codeine salts worldwide.
Codeine is usually present in raw opium as free alkaloid in addition to codeine meconate,
codeine pectinate, and possibly other naturally-occurring codeine salts. Codeine bitartrate,
tartrate, nitrate, picrate, acetate, hydrobromide and others are occasionally encountered on the
pharmaceutical market and in research.

In certain jurisdictions, codeine is available over-the-counter to be sold at the pharmacist's

discretion.

[edit] Relation to other opiates

Codeine is the starting material and prototype of a large class of mainly mild to moderately
strong opioids such as hydrocodone, dihydrocodeine, and its derivatives such as nicocodeine.
Other series of codeine derivatives include isocodeine and its derivatives, which were developed
in Germany starting around 1920. As an analgesic, codeine compares moderately to other
opiates. Related to codeine in other ways are Codeine-N-Oxide (Genocodeine), related to the
nitrogen morphine derivatives as is codeine methobromide, and heterocodeine, which is a drug
six times stronger than morphine and 72 times stronger than codeine due to a small re-
arrangement of the molecule, viz. moving the methyl group from the 3 to the 6 position on the
morphine carbon skeleton. Drugs bearing resemblance to codeine in effects due to close
structural relationship are variations on the methyl groups at the 3 position including
ethylmorphine a.k.a. codethyline (Dionine) and benzylmorphine (Peronine). While having no
narcotic effects of its own, the important opioid precursor thebaine differs from codeine only
slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in
medicine are found in trace amounts in opium as well.

[edit] Adverse effects

Common effects other than analgesia associated with the use of codeine include euphoria,
itching, nausea, vomiting, drowsiness, dry mouth, miosis, orthostatic hypotension, urinary
retention, depression and constipation.[17] Another side effect commonly noticed is the lack of
sexual drive and increased complications in erectile dysfunction.[18] Some people may also have
an allergic reaction to codeine, such as the swelling of skin and rashes.[18] Erectile dysfunction
and diminished libido can be a longer-term effect (years to decades) of many narcotic analgesics
due to development of central hypogonadism; this appears to be an especially common effect of
methadone. The observation that acute effects of codeine, dihydrocodeine, oxycodone,
hydrocodone, morphine and include an increase in libido in women and a plurality of men has
been made ab initio for the aforementioned and for 2500 years or longer with opium—
presumably anxiolysis, euphoria, effects of co-administered substances like caffeine, and
environmental factors are involved.

Codeine and morphine as well as opium were used for control of diabetes until relatively
recently, and still in rare cases in some countries, and the hypoglycaemic effect of codeine,
although usually weaker than that of morphine, diamorphine, or hydromorphone, can lead to
cravings for sugar.

Tolerance to many of the effects of codeine develops with prolonged use, including therapeutic
effects. The rate at which this occurs develops at different rates for different effects, with
tolerance to the constipation-inducing effects developing particularly slowly for instance.

A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This
depression is dose-related and is the mechanism for the potentially fatal consequences of
overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in
potentially lethal amounts, fatally depressing the respiration of a breastfed baby.[19][20]

[edit] Withdrawal effects

As with other opiate-based pain killers, chronic use of codeine can cause physical dependence.
When physical dependence has developed, withdrawal symptoms may occur if a person
suddenly stops the medication. Withdrawal symptoms include: drug craving, runny nose,
yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle
spasms, chills, irritability, and pain. To minimize withdrawal symptoms, long-term users should
gradually reduce their codeine medication under the supervision of a healthcare professional.[21]
A support group called Codeine Free exists to help people who have found themselves dependent
on codeine.

[edit] Recreational use

Codeine can be used as a recreational drug.

In some countries, cough syrups and tablets containing codeine are available without
prescription; some potential recreational users are reported to buy codeine from multiple
pharmacies so as not to arouse suspicion. A heroin addict may use codeine to ward off the effects
of a withdrawal.[22]

Codeine is also available in conjunction with the anti-nausea medication promethazine in the
form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine
with codeine. Called 'syrup', this medication is quickly becoming one of the most highly abused
codeine preparations.[23]

Codeine is also demethylated by reaction with pyridine to illicitly synthesize morphine. Pyridine
is toxic and possibly carcinogenic, so morphine illicitly produced in this manner (and potentially
contaminated with pyridine) may be particularly harmful.[24] Codeine can also be turned into α-
chlorocodide, which is used in the clandestine synthesis of desomorphine (Permonid).

[edit] Detection of use

Codeine and/or its major metabolites may be quantitated in blood, plasma or urine to monitor
therapy, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Drug
abuse screening programs generally test urine, hair, sweat or oral fluid. Many commercial opiate
screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but
chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is
important to note that codeine usage results in significant amounts of morphine as an excretion
product. Furthermore, heroin contains codeine (or acetylcodeine) as an impurity and its use will
result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of
low levels of codeine in one's biofluids. Blood or plasma codeine concentrations are typically in
the 50-300 µg/L range in persons taking the drug therapeutically, 700-7000 µg/L in abusers and
1000–10,000 µg/L in cases of acute fatal overdosage.[25][26][27]

[edit] Controlled substance

In Australia, Canada, New Zealand, Romania, Sweden, the United Kingdom, the United States,
and many other countries, codeine is regulated under various narcotic control laws. In some
countries it is available without prescription in combination preparations from licensed
pharmacists in doses up to 15 mg/tablet in Australia, New Zealand, Poland (Thiocodin, Antidol),
Romania (Codamin), and Costa Rica, 12.8  mg/tablet in the UK, 10 mg/tablet in Israel and
8 mg/tablet in Canada and Estonia.[citation needed]

[edit] North America

[edit] Narcotic content numbers (US & Canada)

The narcotic content number in the US names of codeine tablets and combination products like
Tylenol With Codeine No. 3, Emprin With Codeine No. 4, and pure codeine tablets are as
follows: No. 1 - 7½ or 8 mg (1/8 grain), No. 2 - 15 or 16 mg (1/4 grain), No. 3 - 30 or 32 mg (1/2
grain), No. 4 - 60 or 64 mg (1 grain). The Canadian "Frosst 222"[28] series is identical to the
above list: "222" contains 8 mg codeine, "282" 15 mg, "292" 30 mg, and "293" 60 mg. This
system, which is also used at present in the trade names of some dihydrocodeine and
ethylmorphine products both in and outside of North America, was inaugurated with the Pure
Food and Drug Act of 1906 and related legislation and refined since.

Equivalent scales for labeling stronger opioids such as diacetylmorphine (heroin), morphine,
opium salts mixtures, and others were in common use in the past, and on occasion one can find
past references to brand names for hydrocodone (invented 1920, introduced in US 1943),
hydromorphone (invented 1924), oxycodone (invented 1916), paregoric and similar drugs
containing narcotic content numbers. For example. from circa 1900 to 1925, the most common
cough medicine was terpin hydrate With Heroin Elixir No. 2.

Contrary to the advertising matter of some pharmacies, 60 mg is No. 4, not No. 6, and tablets
with 45 mg of codeine are not No. 4 and would in all likelihood be classified as No. 3½ under
that system. Whether the scale goes to No. 5 and higher is moot at this point, as in the United
States and Canada single-dose-unit concentrations of more than 64 mg are not manufactured.
The United States Controlled Substances Act of 1970 does place dosage unit strengths of 90 mg
of codeine and higher in Schedule II, even if mixed with another active ingredient. Oral tablets,
hypodermic tablets, liquid forms, and capsules of less common doses such as 5, 10, 12, 20, 25,
40, 45, 50, 75, 80, 90, 96, 100, 105, 120 and 128 mg and others and in some cases the equivalent
dihydrocodeine, dionine, benzylmorphine, and opium dosages were previously available in
North America (and in most cases still are in other countries, particularly the 45 mg
paracetamol/codeine and 50 and 100 mg single-ingredient codeine tablets).

[edit] Canada

In Canada, codeine preparations must be sold only at a pharmacy and be either behind the
dispensing counter (or elsewhere, like in a back room) or on shelves in an area of the store that
can be seen from the dispensing counter. Further, codeine can be sold over the counter only in
combination with two or more ingredients, which has resulted in the prevalence of co-codaprin
(or "AC&C"), which contains acetylsalicylic acid (ASA), codeine, and caffeine, and similar
combinations using acetaminophen (paracetamol) rather than acetylsalicylic acid (aspirin).
Caffeine, being a stimulant, tends to offset the sedative effects of codeine. It also can increase the
effectiveness and absorption rate of analgesics in some circumstances.[29] Co-codaprin containing
8 mg codeine is often requested and sold as "Frosst 222" at pharmacies, where it is generally
available over the counter. Formulations containing more than 8 mg of codeine are available by
prescription only.

[edit] United States

Codeine cough syrup with promethazine being poured over ice. Texas, 2011.

In the United States, codeine is regulated by the Controlled Substances Act. It is a Schedule II
controlled substance for pain-relief products containing codeine alone or more than 90 mg per
dosage unit. Tablets of codeine in combination with aspirin or acetaminophen
(paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are
Schedule III or V, depending on formula. The acetaminophen/codeine pain-relief elixir (trade
name Tylenol Elixir with Codeine) is a Schedule V controlled substance.[30]

Preparations for cough or diarrhea containing small amounts of codeine in combination with two
or more other active ingredients are Schedule V in the US, and in some states may be dispensed
in amounts up to 4 fl. oz. per 48 hours (one or two states set the limit at 4 fl. oz. per 72 hours)
without a prescription. Schedule V specifically consigns the product to state and local regulation
beyond certain required record-keeping requirements (a dispensary log must be maintained for
two years in a ledger from which pages cannot easily be removed and/or are pre-numbered, and
the pharmacist must ask for a picture ID such as a driving licence) and also maintain controlled
substances in the closed system at the root of the régime intended by the Controlled Substances
Act of 1970; the codeine in these products was a Schedule II substance when the company
making the Schedule V product acquired it for mixing up the end-product.

In locales where dilute codeine preparations are non-prescription, anywhere from very few to
perhaps a moderate percentage of pharmacists will sell these preparations without a prescription.
However, many states have their own laws that do require a prescription for Schedule V drugs.
The December 2008 issue of The Bulletin of the National Codeine OTC Lobby (Vol. XVIII, No.
4) listed 12 states with some kind of OTC access to codeine, noting that small independent
pharmacies are the most likely to have it. This situation is roughly equivalent to that in February
1991, when the aforementioned organisation undertook its first comprehensive study of Schedule
V and overall codeine, dihydrocodeine, ethylmorphine, and hydrocodone availability.
Other drugs that are present in Schedule V narcotic preparations like the codeine syrups are
ethylmorphine and dihydrocodeine. Paregoric and hydrocodone were transferred to Schedule III
from Schedule V even if the preparation contains two or more other active ingredients, and
diphenoxylate is usually covered by state prescription laws even though this relative of pethidine
is a Schedule V substance when adulterated with atropine to prevent abuse.

Codeine is also available outside the United States as an over-the-counter drug in liquid cough-
relief formulations.[verification needed] Around the world, codeine is, contingent on its concentration, a
Schedule II and IV drug under the Single Convention on Narcotic Drugs.[31]

[edit] Australia

In Australia, codeine preparations must be sold only at a pharmacy. The item is given over the
counter, no prescriptions. The strongest available over the counter preparation containing
codeine has 15 mg (with paracetamol, brand name Panadeine Extra), anything stronger requires a
prescription.[32]

[edit] Germany, Switzerland and Austria

Codeine is listed under the Betäubungsmittelgesetz in Germany and the similarly-named

narcotics and controlled substances law in Switzerland. In Austria, the drug is listed under the
Suchtmittelgesetz in categories corresponding to their classification under the Single Convention
on Narcotic Drugs. Dispensing of products containing codeine and similar drugs
(dihydrocodeine, nicocodeine, benzylmorphine, ethylmorphine etc.), in general, require a
prescription order from a doctor or the discretion of the pharmacist. Municipal and provincial
regulations may impact availability, in particular in Austria and Switzerland, which allows cities
and provinces to regulate the selling of the least-regulated schedule of the SMG/BtMG; and, of
course, individual chemists' shops can opt out of providing them or imposing volume, frequency,
or single-purchase limitations and other things of the same store. Plain codeine hydrochloride
tablets (which in the USA would share CSA Schedule II with drugs like morphine, cocaine,
hydromorphone, and bezitramide) as well as other non-injectable forms of codeine and its
midrange derivatives can be dispensed in this way; the same goes for most chemical classes of
benzodiazepines, the majority of non-barbiturate sedative/hypnotics, and at least a handful of
barbiturates.

Title 76 of the Schengen treaty has made it possible for countries within the signatory states to
import and export drugs with various provisos, recording and ordering requirements, and various
other rules.

[edit] France

In France, most preparations containing codeine do not require a doctor's prescription. Example
products containing codeine include Néocodeion (cough pills), Codoliprane (codeine with
paracetamol) and Prontalgine (codeine, paracetamol and caffeine).[33]

[edit] Greece
Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably
be arrested, even if they were legitimately prescribed it in another country.[34]

[edit] Hong Kong

In Hong Kong, codeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous
Drugs Ordinance. It can be used legally only by health professionals and for university research
purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies
the substance without prescription can be fined $10,000 (HKD). The maximum penalty for
trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment.
Possession of the substance for consumption without license from the Department of Health is
illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

However, codeine is available without prescription from licensed pharmacists in doses up to

0.1% (5 mg/5ml) according to Hong Kong "Dangerous Drugs Ordinance".

[edit] Ireland

In the Republic of Ireland, new regulations came into effect on August 1, 2010[35] concerning
codeine, due to worries about the overuse of the drug. Codeine remains an non-prescriptive,
over-the-counter drug, but codeine products must be out of the view of the public, to facilitate
the legislative requirement that these products “are not accessible to the public for self-
selection”.[36] In practice, this means customers must ask pharmacists for the product containing
codeine in name, and the pharmacist makes a judgement whether it is suitable for the patient to
be using codeine, and that patients are fully advised of the correct use of these products.[37]

[edit] Italy

Codeine tablets or preparations require a prescription in Italy. A preparation of paracetamol and

codeine is available in Italy as CoEfferalgan.

[edit] Japan

Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics,
antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal
preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC
dispensing. This is also true of ethylmorphine and dihydrocodeine, and also diphenoxylate, some
weak relatives of the thiambutene opioid family.

[edit] Spain

Codeine tablets or preparations require a prescription in Spain although it's often not enforced
and many pharmacies will sell codeine products without the requirement of a prescription.

[edit] Turkey
Codeine is available by a doctor's prescription. It is still possible to find some pharmacies who
sell codeine without any prescription. In big cities, pharmacies often don't sell the drug at all. For
OTC codeine containing combinations, the choice is up to the pharmacist.[citation needed]

[edit] United Kingdom

In the United Kingdom, higher-strength codeine formulations - such as 30/500 co-codamol,

where 30 mg of codeine phosphate is combined with 500 mg paracetamol - are prescription-only
medicines (POM). Lower-strength combinations, such as 8/500 (various brands) or 12.8/500
(Panadol Ultra, Solpadeine MAX and others) are available as pharmacy supervised ("behind the
counter") medicines. Codeine is also available combined with Ibuprofen; a common formulation
is 12.8 mg Codeine alongside 200 mg [Link] is also available 'behind the counter' with
aspirin in doses of 8 mg Codeine phosphate and 500Mg aspirin (Codis). Codeine Linctus of
15 mg per 5ml is also available behind the counter at some pharmacies, although a purchaser
would have to request it specifically from the pharmacist. Intramuscular injection of codeine is a
controlled drug under the Misuse of Drugs Act 1971.

Kodeina
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Struktur kimia kodeina.

Kodeina atau kodein (bahasa Inggris: codeine, methylmorphine) ialah asam opiat alkaloid yang
dijumpai di dalam candu dalam konsentrasi antara 0,7% dan 2,5%. Kebanyakan kodein yang
digunakan di Amerika Serikat diproses dari morfin melalui proses metilasi.

Kodein yang terkonsumsi akan teraktivasi oleh enzim CYP2D6[1] di dalam hati[2] menjadi morfin,
sebelum mengalami proses glusuronidasi, sebuah mekanisme detoksifikasi bagi xenobiotik.[3]

Walau bagaimanapun, morfin tersebut tidak dapat digunakan, mengingat 90% kodein yang
diambil akan dimusnahkan dalam usus halus (rembesan dari hati) sebelum berhasil memasuki
peredaran darah. Oleh itu, kodein seolah-olah tidak brpengaruh atas penggunanya, namun efek
samping seperti analgesia, sedasi, dan kemurungan pernafasan masih terasa.

Kodein digunakan sebagai peredam sakit ringan. Kodein selalu dibuat dalam bentuk pil atau
cairan dan bisa diambil baik secara sendirian atau gabungan dengan kafein, aspirin,
asetaminofen, atau ibuprofen. Kodein sangat berperan untuk meredakan batuk.

Seperti semua jenis opioid, penggunaan kodeina yang berkelanjutan mengakibatkan

ketergantungan secara fisik dan psikologi. Sebuah kelompok yang bernama Codeine Free
didirikan untuk membantu mereka yang mengalami ketergantungan pada kodeina.

Kodein merupakan obat yang paling banyak digunakan dalam perawatan kesehatan.

Bioavailability 68–72%(Increases with repeat dosing.)

Protein binding 20%
Metabolism Hepatic demethylation and glucuronidation
Half-life 5.5–7 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. C(AU) C(US)
Prescription Only (S4) (AU) POM (UK) ℞-only
Legal status
(US) ℞ Prescription only
oral, IV, IM, rectal, sublingual, buccal,
Routes
intranasal
  (what is this?)  (verify)

Tramadol hydrochloride (Ultram, Tramal others below) is a centrally acting opioid analgesic,
used in treating moderate to severe pain. The drug has a wide range of applications, including
treatment for restless leg syndrome and fibromyalgia. It was developed by the pharmaceutical
company Grünenthal GmbH in the late 1970s.[1][2]

Tramadol possesses weak agonist actions at the μ-opioid receptor, releases serotonin, and
inhibits the reuptake of norepinephrine.[3][4][5][6][7][8][9]
Tramadol is a synthetic analog of the phenanthrene alkaloid codeine and, as such, is an opioid
and also a prodrug (codeine is metabolized to morphine, tramadol is converted to O-
desmethyltramadol). Opioids are chemical compounds which act upon one or more of the human
opiate receptors. The euphoria and respiratory depression are mainly caused by the μ1 and μ2
receptors; the addictive nature of the drug is due to these effects as well as its
serotonergic/noradrenergic effects. The opioid agonistic effect of tramadol and its major
metabolite(s) are almost exclusively mediated by the substance's action at the μ-opioid receptor.
This characteristic distinguishes tramadol from many other substances (including morphine) of
the opioid drug class, which generally do not possess tramadol's degree of subtype selectivity.

Contents
[hide]

 1 Uses
o 1.1 Availability and usage
o 1.2 Off-label and investigational uses
o 1.3 Veterinary
 2 Pregnancy and breastfeeding
 3 Adverse effects and drug interactions
 4 Chemistry
o 4.1 Characteristics
o 4.2 Comparison with related substances
o 4.3 Synthesis and stereoisomerism
 5 Metabolism
 6 Mechanism of action
 7 Abuse and dependency
o 7.1 Physical dependence and withdrawal
o 7.2 Psychological dependence and drug misuse
o 7.3 Detection in biological fluids
 8 Legal status
 9 Proprietary preparations
 10 See also
 11 Notes
 12 External links

[edit] Uses
Tramadol is used similarly to codeine, to treat moderate to moderately severe pain and most
types of neuralgia, including trigeminal neuralgia.[10] Tramadol is somewhat pharmacologically
similar to levorphanol (albeit with much lower μ-agonism), as both opioids are also NMDA-
antagonists which also have SNRI activity (other such opioids to do the same are
dextropropoxyphene (Darvon) & M1-like molecule tapentadol (Nucynta, a new synthetic
atypical opioid made to mimic the agonistic properties of tramadol's metabolite, M1(O-
Desmethyltramadol). Tramadol is also molecularly similar to Effexor (Venlafaxine) and has
similar SNRI effects, with antinociceptive effects also observed. It has been suggested that
tramadol could be effective for alleviating symptoms of depression, anxiety, and phobias[11]
because of its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid
activity.[12] However, health professionals have not endorsed its use for these disorders,[13][14]
claiming it may be used as a unique treatment (only when other treatments failed), and must be
used under the control of a psychiatrist.[15][16]

In May 2009, the United States Food and Drug Administration issued a Warning Letter to
Johnson & Johnson, alleging that a promotional website commissioned by the manufacturer had
"overstated the efficacy" of the drug, and "minimized the serious risks".[17] The company which
produced it, the German pharmaceutical company Grünenthal GmbH, were the ones alleged to
be guilty of "minimizing" the addictive nature and proposed efficacy of the drug, although it
showed little abuse liability in preliminary tests. The 2010 Physicians Desk Reference contains
several warnings from the manufacturer, which were not present in prior years. The warnings
include more compelling language regarding the addictive potential of tramadol, the possibility
of difficulty breathing while on the medication, a new list of more serious side effects, and a
notice that tramadol is not to be used in place of opiate medications for addicts. Tramadol is also
not to be used in efforts to wean addict patients from opiate drugs, nor to be used to manage
long-term opiate addiction.

[edit] Availability and usage

Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride); the tartrate is
seen on rare occasions, and rarely (in the US at least) tramadol is available for both injection
(intravenous and/or intramuscular) and oral administration. The most well known dosing unit is
the 50 mg generic tablet made by several manufacturers. It is also commonly available in
conjunction with APAP (Paracetamol, Acetaminophen) as Ultracet, in the form of a smaller dose
of 37.5 mg tramadol and 325 mg of APAP. The solutions suitable for injection are used in
patient-controlled analgesia pumps under some circumstances, either as the sole agent or along
with another agent such as morphine.

Tramadol comes in many forms, including:

 capsules (regular and extended release)

 tablets (regular, extended release, chewable, low-residue and/or uncoated tablets that can
be taken by the sublingual and buccal routes)
 suppositories
 effervescent tablets and powders
 ampules of sterile solution for SC, IM, and IV injection
 preservative-free solutions for injection by the various spinal routes (epidural, intrathecal,
caudal, and others)
 powders for compounding
  liquids both with and without alcohol for oral and sub-lingual administration, available in
regular phials and bottles, dropper bottles, bottles with a pump similar to those used with
liquid soap and phials with droppers built into the cap
 tablets and capsules containing (acetaminophen/APAP), aspirin and other agents.

Tramadol has been experimentally used in the form of an ingredient in multi-agent topical gels,
creams, and solutions for nerve pain, rectal foam, concentrated retention enema, and a skin
plaster (transdermal patch) quite similar to those used with lidocaine.

Tramadol has a characteristic and unpleasant taste which is mildly bitter but much less so than
morphine and codeine. Oral and sublingual drops and liquid preparations come with and without
added flavoring. Its relative effectiveness via transmucosal routes (i.e. sublingual, buccal, rectal)
is similar to that of codeine, and, like codeine, it is also metabolized in the liver to stronger
metabolites (see below).

The maximum dosage per day is 400 mg for oral use and 600 mg for parenteral use. Certain
manufacturers or formulations have lower maximum doses. For example, Ultracet
(37.5 mg/325 mg tramadol/APAP tablets) is capped at 8 tablets per day (300 mg/day) due to its
acetaminophen content. Ultram ER is available in 100, 200, and 300 mg/day doses and is
explicitly capped at 300 mg/day as well.

Patients taking SSRIs (Prozac, Zoloft, etc.), SNRIs (Effexor, etc.), TCAs, MAOIs, or other
strong opioids (oxycodone, methadone, fentanyl, morphine), as well as the elderly (> 75 years
old), pediatric (< 18 years old), and those with severely reduced renal (kidney) or hepatic (liver)
function should consult their doctor regarding adjusted dosing or whether to use Tramadol at all.

[edit] Off-label and investigational uses

 diabetic neuropathy [18][19]
 postherpetic neuralgia [20][21]
 fibromyalgia [22]
 restless legs syndrome [23]
 opiate withdrawal management[24][25] /Anti-Depressant withdrawal aid (proven to be
effective, especially with withdrawal from its distant relative Venlafaxine(Effexor)).
 migraine headache[26]
 obsessive-compulsive disorder [27]
 premature ejaculation [28]

[edit] Veterinary

Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related)
pain in dogs and cats[29] as well as rabbits, coatis, many small mammals including rats and flying
squirrels, guinea pigs, ferrets, and raccoons. Tramadol comes in ampules in addition to the
tablets, capsules, powder for reconstitution, and oral syrups and liquids; the fact that its
characteristic taste is distasteful to dogs, but can be masked in food, makes for a means of
administration. No data that would lead to a definitive determination of the efficacy and safety of
tramadol in reptiles or amphibians is available at this time, and, following the pattern of all other
drugs, it appears that tramadol can be used to relieve pain in marsupials such as North American
opossums, Short-Tailed Opossums, sugar gliders, wallabies, and kangaroos among others.

Tramadol for animals is one of the most reliable and useful active principles available to
veterinarians for treating animals in pain. It has a dual mode of action: mu agonism and mono-
amine reuptake inhibition, which produces mild anti-anxiety results. Tramadol may be utilized
for relieving pain in cats and dogs. This is an advantage because the use of some non-steroidal
anti-inflammatory substances in these animals may be dangerous.

When animals are administered tramadol, adverse reactions can occur. The most common are
constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint
pupils and seizures may appear. In such case, veterinarians should evaluate the correct treatment
for these events. Some contraindications have been noted in treated animals taking certain other
drugs. Tramadol should not be co-administered with selegiline or any other psychoactive class of
medication such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, or
monoamine oxidase inhibitors. In animals, tramadol is removed from the body via liver and
kidney excretion. Animals suffering from diseases in these systems should be monitored by a
veterinarian, as it may be necessary to adjust the dose.

Dosage and administration of tramadol for animals: in dogs for sufficient analgesia: 1–4 mg/kg
PO q8-12h (Hardie, Lascelles et al. 2003) and to control chronic pain in cats: 4 mg/kg PO twice
daily (Note: Dose extrapolated from human medicine. Tramadol has not been evaluated for
toxicity in cats and has not been used extensively, but early results encouraging) (Lascelles,
Robertson et al. 2003).

[edit] Pregnancy and breastfeeding

Tramadol is in FDA pregnancy category C; animal studies have shown its use to be dangerous
during pregnancy and human studies are lacking. Therefore, the drug should not be taken by
women that are pregnant unless "the potential benefits outweigh the risks".[30]

Tramadol causes serious or fatal side-effects in a newborn[31] including neonatal withdrawal, if

the mother uses the medication during pregnancy or labor. Use of tramadol by nursing mothers is
not recommended by the manufacturer because the drug passes into breast milk.[30] However, the
absolute dose excreted in milk is quite low, and tramadol is generally considered to be acceptable
for use in breastfeeding mothers when absolutely necessary.[32]

[edit] Adverse effects and drug interactions

Main side effects of tramadol. Red color denotes more serious effects, requiring immediate
contact with health provider.[33]

The most commonly reported adverse drug reactions are nausea, vomiting, sweating, itching and
constipation. Drowsiness is reported, although it is less of an issue than for non-synthetic
opioids. Patients prescribed tramadol for general pain relief with or without other agents have
reported withdrawal symptoms including uncontrollable nervous tremors, muscle contracture,
and 'thrashing' in bed (similar to restless leg syndrome) if weaning off the medication happens
too quickly. Anxiety, 'buzzing', 'electrical shock' and other sensations may also be present,
similar to those noted in Effexor withdrawal. Anecdotally, tramadol is widely regarded by
chronic pain sufferers as being among the most difficult of the pain medications to stop after
prolonged administration, as withdrawal from both the serotonergic/noradrenergic and the mu-
opioid effects is present. Respiratory depression, a common side-effect of most opioids, is not
clinically significant in normal doses. By itself, it can decrease the seizure threshold. When
combined with SSRIs, tricyclic antidepressants, or in patients with epilepsy, the seizure threshold
is further decreased. Seizures have been reported in humans receiving excessive single oral doses
(700 mg) or large intravenous doses (300 mg). However, there have been several rare cases of
people having grand-mal seizures at doses as low as 100–400 mg orally.[34][35][36] An Australian
study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and
that in the authors' First Seizure Clinic, "tramadol is the most frequently suspected cause of
provoked seizures".[37] There appears to be growing evidence that Tramadol use may have
serious risks in some individuals and it is contra-indicated in patients with uncontrolled epilepsy
(BNF 59). Seizures caused by tramadol are most often tonic-clonic seizures, more commonly
known in the past as grand mal seizures. Also when taken with SSRIs, there is an increased risk
of serotonin toxicity, which can be fatal. Fewer than 1% of users have a presumed incident
seizure claim after their first tramadol prescription. Risk of seizure claim increases 2- to 6-fold
among users adjusted for selected comorbidities and concomitant drugs. Risk of seizure is
highest among those aged 25–54 years, those with more than four tramadol prescriptions, and
those with a history of alcohol abuse, stroke, or head injury.[38] Dosages of warfarin may need to
be reduced for anticoagulated patients to avoid bleeding complications. Constipation can be
severe especially in the elderly requiring manual evacuation of the bowel.[citation needed] Furthermore,
there are suggestions that chronic opioid administration may induce a state of immune tolerance,
[39]
although tramadol, in contrast to typical opioids may enhance immune function.[40][41][42] Some
have also stressed the negative effects of opioids on cognitive functioning and personality.[43]

Probability of Occurrence of Various Adverse Effects[44]

Effect Probability (%)
Any adverse effect 71
Drowsiness 17
Nausea 17
Dizziness 15
Constipation 11
Headache 11
Vomiting 7
Diarrhea 6
Dry Mouth 5
Fatigue 5
Indigestion 5
[38]
Seizure <1

[edit] Chemistry
[edit] Characteristics

Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and
tramadol share the 3-methyl ether group, and both compounds are metabolized along the same
hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this
is morphine, and for tramadol, it is the O-desmethyltramadol.

[edit] Comparison with related substances

Structurally, tapentadol is the closest chemical relative of tramadol in clinical use. Tapentadol is
also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one
stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and
venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a
phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety,
attached directly to the aromatic, while tapentadol lacks this feature. In reality, the closest
structural chemical entity to tapentadol in clinical use is the over-the-counter drug
phenylephrine. Both share a meta phenol, attached to a straight chain hydrocarbon. In both cases,
the hydrocarbon terminates in an amine.

[edit] Synthesis and stereoisomerism

  
(1R,2R)-Tramadol     (1S,2S)-Tramadol

 
(1R,2S)-Tramadol     (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.[45] Tramadol [2-

(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the
cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist
in four different configurational forms:

 (1R,2R)-isomer
 (1S,2S)-isomer
 (1R,2S)-isomer
 (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-
isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and
the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-
isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized
by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the
hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the
racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described[46] employing (R)-(–)- or (S)-
(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a
racemate, despite known different physiological effects [47] of the (1R,2R)- and (1S,2S)-isomers,
because the racemate showed higher analgesic activity than either enantiomer in animals[48] and
in humans.[49]

[edit] Metabolism
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6
and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, O-
desmethyltramadol is the most significant since it has 200 times the μ-affinity of (+)-tramadol,
and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol
itself. In the 6% of the population that have slow CYP2D6 activity, there is therefore a slightly
reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble,
which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic
impairment.[50]

[edit] Mechanism of action

Tramadol acts as a μ-opioid receptor agonist,[51][52] serotonin releasing agent,[6][7][8][9]
norepinephrine reuptake inhibitor,[52] NMDA receptor antagonist,[53] 5-HT2C receptor antagonist,
[54] [55]
(α7)5 nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist,[56] and M1 and M3
[57][58]
muscarinic acetylcholine receptor antagonist.

The analgesic action of tramadol has yet to be fully understood, but it is believed to work
through modulation of serotonin and norepinephrine in addition to its mild agonism of the μ-
opioid receptor. The contribution of non-opioid activity is demonstrated by the fact that the
analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist
naloxone.

Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak
affinity for the μ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil,
2006). The (1R,2R)-(+)-enantiomer is approximately four times more potent than the (1S,2S)-(–)-
enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1S,2S)-(–)-
enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions
appear to produce a synergistic analgesic effect, with (1R,2R)-(+)-tramadol exhibiting 10-fold
higher analgesic activity than (1S,2S)-(–)-tramadol (Goeringer et al., 1997).

The serotonergic-modulating properties of tramadol give tramadol the potential to interact with
other serotonergic agents. There is an increased risk of serotonin toxicity when tramadol is taken
in combination with serotonin reuptake inhibitors (e.g., SSRIs), since these agents not only
potentiate the effect of 5-HT but also inhibit tramadol metabolism.[citation needed] Tramadol is also
thought to have some NMDA antagonistic effects, which has given it a potential application in
neuropathic pain states.

Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially
responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in
patients with pain and co-morbid neurological illnesses.[59] 5-HT2C blockade may also account for
its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased
vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the
reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABA-A
receptors at high doses.[53]

The overall analgesic profile of tramadol supports intermediate pain, especially chronic states. It
is slightly less effective for acute pain than hydrocodone, but more effective than codeine. It has
a dosage ceiling similar to codeine, a risk of seizures when overdosed, and a relatively long half-
life making its potential for abuse relatively low amongst intermediate strength analgesics.

Tramadol's primary active metabolite, O-desmethyltramadol, is a considerably more potent μ-

opioid receptor agonist than tramadol itself, and is so much more so that tramadol can partially
be thought of as a prodrug to O-desmethyltramadol. Similarly to tramadol, O-desmethyltramadol
has also been shown to be a norepinephrine reuptake inhibitor, 5-HT2C receptor antagonist, and
M1 and M3 muscarinic acetylcholine receptor antagonist.[citation needed]

[edit] Abuse and dependency

[edit] Physical dependence and withdrawal

Tramadol is associated with the development of physical dependence and a severe withdrawal
syndrome.[60] Tramadol causes typical opiate-like withdrawal symptoms as well as atypical
withdrawal symptoms including seizures. The atypical withdrawal symptoms are probably
related to tramadol's effect on serotonin and norepinephrine reuptake. Symptoms may include
those of SSRI discontinuation syndrome, such as anxiety, depression, anguish, severe mood
swings, aggressiveness, brain "zaps", electric-shock-like sensations throughout the body,
paresthesias, sweating, palpitations, restless legs syndrome, sneezing, insomnia, tremors, and
headache among others. In most cases, tramadol withdrawal will set in 12–20 hours after the last
dose, but this can vary. Tramadol withdrawal lasts longer than that of other opioids; seven days
or more of acute withdrawal symptoms can occur as opposed to typically three or four days for
other codeine analogues. It is recommended that patients physically dependent on pain killers
take their medication regularly to prevent onset of withdrawal symptoms and this is particularly
relevant to tramadol because of its SSRI and SNRI properties, and, when the time comes to
discontinue their tramadol, to do so gradually over a period of time that will vary according to
the individual patient and dose and length of time on the drug.[61][62][63][64]

[edit] Psychological dependence and drug misuse

Some controversy regarding the abuse potential of tramadol exists. Grünenthal has promoted it
as an opioid with a lower risk of opioid dependence than that of traditional opioids, claiming
little evidence of such dependence in clinical trials (which is true, Grünenthal never claimed it to
be non-addictive). They offer the theory that, since the M1 metabolite is the principal agonist at
μ-opioid receptors, the delayed agonist activity reduces abuse liability. The norepinephrine
reuptake inhibitor effects may also play a role in reducing dependence.

It is apparent in community practice that dependence to this agent may occur after as little as
three months of use at the maximum dose—generally depicted at 400 mg per day. However, this
dependence liability is considered relatively low by health authorities, such that tramadol is
classified as a Schedule 4 Prescription Only Medicine in Australia, and been rescheduled in
Sweden rather than as a Schedule 8 Controlled Drug like opioids.[65] Similarly, tramadol is not
currently scheduled by the U.S. DEA, unlike opioid analgesics. It is, however, scheduled in
certain states.[66] Nevertheless, the prescribing information for Ultram warns that tramadol "may
induce psychological and physical dependence of the morphine-type".
Dependence on Tramadol has been reported to be a major social problem in the Gaza Strip. The
Hamas government has attempted to cut off supplies of the drug, and in April 2010 burnt 2
million tablets which had been intercepted while being smuggled into the territory.[67]

Due to the possibility of convulsions at high doses for some users, recreational use can be very
dangerous.[68] Tramadol can, however, via agonism of μ opioid receptors, produce effects similar
to those of other opioids (Codeine and other weak opioids), although not nearly as intense due to
tramadol's much lower affinity for this receptor. Tramadol can cause a higher incidence of
nausea, dizziness, loss of appetite compared with opiates which could deter abuse to some
extent.[69] Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier
to lower the quantity of its usage, compared with opioids such as hydrocodone and oxycodone.[70]
It may also have large effect on sleeping patterns and high doses may cause insomnia.

 (Especially for those on methadone, both for maintenance and recreation. Though there is
no scientific proof tramadol lessens effects or is a mixed agonist-antagonist, some people
get the impression it is, while someone else might benefit being prescribed both for pain
and B/T pain)[71]

Tramadol can cause withdrawal symptoms in people who are at the time intoxicated from
methadone.[72]

[edit] Detection in biological fluids

Tramadol and O-desmethyltramadol may be quantitated in blood, plasma or serum to monitor for
abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other
criminal violation or a sudden death. Most commercial opiate immunoassay screening tests do
not cross-react significantly with tramadol or its major metabolites, so chromatographic
techniques must be used to detect and quantitate these substances. The concentrations of O-
desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10-
20% those of the parent drug.[73][74][75]

[edit] Legal status

Tramadol is a controlled substance in some US states and Canada, and requires a prescription.
However, Tramadol is readily available by remote prescription including via internet pharmacies
with relative ease. As of December 5, 2008, Kentucky has classified tramadol as a Schedule IV
controlled substance.[66] The Military Pain Care Act of 2008 requires on base pharmacies to label
tramadol as a controlled substance.[76]

Tramadol is available over the counter without prescription in a few countries.[77] Sweden, as of
May 2008, has chosen to classify tramadol as a controlled substance in the same way as codeine
and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine
and dextropropoxyphene, a normal prescription can be used at this time.[78] In Mexico, combined
with paracetamol and sold under the brand name Tramacet, it is widely available without a
prescription. In most Asian countries such as the Philippines, it is sold as a capsule under the
brand name Tramal, where it is mostly used to treat labor pains.
Tramadol (as the racemic, cis-hydrochloride salt), is available as a generic in the U.S. from any
number of different manufacturers, including Caraco, Mylan, Cor Pharma, Mallinckrodt, Pur-
Pak, APO, Teva, and many more. Typically, the generic tablets are sold in 50 mg tablets. Brand
name formulations include Ultram ER, and the original Ultram from Ortho-McNeil (cross-
licensed from Grünenthal GmbH). The extended-release formulation of tramadol—which,
amongst other factors—was intended to be more abuse-deterrent than the instant release)
allegedly possesses more abuse liability than the instant release formulation.[citation needed] The U.S.
Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-
release (ER) formulation in September 2005.[79] It is covered by U.S. patents nos. 6,254,887[80]
and 7,074,430.[81][82] The FDA lists the patents as scheduled for expiration on May 10, 2014.[81]
However, in August 2009, U.S. District Court for the District of Delaware ruled the patents
invalid, which, if it survives appeal, would permit manufacture and distribution of generic
equivalents of Ultram ER in the United States.[83]