January 30th, 2009

Tramadol
Systematic (IUPAC) name
(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
Identifiers
CAS number	27203-92-5
ATC code	NO2AX02
PubChem	33741
DrugBank	APRD00028
ChemSpider	31105
Chemical data
Formula	C16H25NO2
Mol. mass	263.4 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	68–72% Increases with repeated dosing.
Protein binding	20%
Metabolism	Hepatic demethylation and glucuronidation
Half life	5–7 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(AU) C(US)
Legal status	Prescription Only (S4)(AU) POM(UK)
Routes	oral, IV, IM, IV, rectal, sublingual, buccal

Tramadol (INN) (pronounced /ˈtræmədɒl/) is a CNS depressant and analgesic, used for treating moderate to severe pain. It is a synthetic agent, and it appears to have actions at the μ-opioid receptor as well as the noradrenergic and serotonergic systems. Tramadol was developed by the Germa pharmaceutical company Grünenthal GmbH in the late 1970s and marketed under the trade name Tramal. Grünenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names such as Ultram and ULTRAM® ER. Tramadol’s chemical structure is quite different from those of opioids. The closest chemical relative of tramadol in clinical use is tapentadol, which is a member of the same chemical class as tramadol and also developed by Grünethal.

Uses

Tramadol is used to treat moderate and severe pain and most types of neuralgia, including trigeminal neuralgia.^{[citation needed]} It has been suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of its action on the noradrenergic and serotonergic systems, the involvement of which appear to play a part in its ability to alleviate the perception of pain. However, health professionals have not yet endorsed its use on a large scale for disorders such as this.

Availability

Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride); the tartrate is seen on rare occasions, and tramadol is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is also available in conjunction with paracetamol (acetaminophen). 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.

Specifically, tramadol comes in many forms, including:

• capsules
• tablets
• extended-release tablets
• extended-release capsules
• chewable tablets
• low-residue and/or uncoated tablets which can be taken by the sublingual and buccal routes
• suppositories
• effervescent tablets and powders
• ampoules 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 sublingual 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 paracetamol (acetaminophen) and asprin 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 enaema, and a skin plaster (transdermal patch) quite similar to those used with lidocaine.

Tramadol has a characteristic 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 flavouring. Its relative effectivness via transmucousal routes (sublingual, buccal, rectal) is around that of codeine and like codeine it is also metabolised in the liver to stronger metabolites (see below).

Dosage

Doses range from 50–400 mg daily, maximum dose of 400 mg a day according to the German package insert for both Grünethal’s product Tramal 100 mg extended-release tablets and the Tramundal (Mundipharma Ges. m.b.H) 100 mg/ml dropper bottles and 100 and 200 ml dosage pump bottles), with up to 600 mg daily when given IV/IM. The formulation containing APAP contains 37.5 mg of tramadol and 325 mg of paracetamol, intended for oral administration with a common dosing recommendation of one or two tablets every four to six hours.

Tramadol responds very well to opioid potentiators used to reduce the amount of medication needed to stop a given level of pain; the most effective appears to be promethazine, which also increases the percentage of the drug changed to stronger active metabolites in the liver as it does with the codeine-based opioid analgesics. Orphenadrine, hydroxyzine, diphenhydramine, chlorpheniramine, carisoprodol and benzodiazepines are commonly-used potentiators for tramadol and other drugs in its range of efficacy. Clonidine can reduce side effects and raise the de facto daily dosage ceiling for tramadol but may also competitively reduce the effects on nerve pain in some patients whilst having no effect or intensifying it in others.

Carbamazepine and some other agents can affect metabolism in such a way that tramadol single and 24-hour doses may have to be increased by as much as 120 per cent to have the same effect. In some patients, use within 15 days prior to starting tramadol can reduce the effectiveness of tramadol by the same Cytochrome p450-related mechanism that causes fluoxetine to wipe out the usefulness of codeine, dihydrocodeine, and similar drugs for a similar period. Combining fluoxetine and tramadol can increase the potential of some tramadol side effects and if done requires very close medical supervision and often can be made less problematic by the addition of a drug with antiseritonergic effects such as cyproheptadine, various phenothiazines, and anticonvulsants if the continuation of fluoxetine is important.

In addition to its use as the primary centrally-acting analgesic, tramadol can also be used with opioids in the place of adjuvants such as duloxetine to help combat neuropathic pain by broadening the spectrum of actions of the primary opioid; this is very useful with morphine, codeine, and its derivatives, somewhat useful with methadone, piritramide, and levorphanol (possibly because tramadol duplicates much more of the spectrum of effects of these drugs) and should be used only very cautiously with and most of its derivatives due to additive effects which can have toxic CNS and peripheral effects. Tramadol can generally be used alongside many other commonly used adjuvants like orphenadrine and related drugs, although those with impacts on seritonin and norepinephrine levels such as amitryptiline, cyclobenzaprine, duloxetine, and MAO inhibitors should be used alongside tramadol with caution and often with reduced doses of both agents.

Off-label and investigational uses

• diabetic neuropathy
• postherpetic neuralgia
• fibromyalgia
• restless legs syndrome
• opiate withdrawal management
• migraine headache
• obsessive-compulsive disorder
• premature ejaculation

Veterinary

Tramadol is used to treat post-operative, injury-related, and chronic (e.g. cancer-related) pain in dogs and cats  as well as rabbits, coatis, many rodents including rats and flying squirrels, guinea pigs, ferrets and raccoons. Tramadol comes in ampoules in addition to the tablets, capsules, powder for reconstitution and oral syrups and liquids; the fact that its characteristic taste is not very bitter and can be masked in food and diluted in water makes for a number of means of administration. No data which 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 amongst others.

Mechanism of action

The mode of action of tramadol has yet to be fully understood, but it is believed to work through modulation of the noradrenergic and serotonergic systems in addition to its mild agonism of the μ-opioid receptor. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the μ-opioid receptor antagonist naloxone.

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

The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs) or with use of a light box, since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. Tramadol is also thought to have some NMDA-type antagonist effects which has given it a potential application in neuropathic pain states.

Metabolism

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme , being O- and N-demethylated to five different metabolites. Of these, M1 (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 who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are excreted by the kidneys. Thus reduced doses may be used in renal and hepatic impairment.

Adverse effects

The most commonly reported adverse drug reactions are nausea, vomiting, sweating and constipation. Drowsiness is reported, although it is less of an issue than for opioids. Patients prescribed tramadol for general pain relief along with other agents have reported uncontrollable withdrawal-like nervous tremors if weaning off the medication happens too quickly. 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). 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” (Labate 2005). Seizures caused by tramadol are most often tonic-clonic seizures, more commonly known in the past as grand mal seizures. Dosages of coumadin/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,  although Tramadol, in contrast to typical opioids may enhance immune function. Some have also stressed the negative effects of opioids on cognitive functioning and personality.

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 who are pregnant unless “the potential benefits outweigh the risks”.

Tramadol causes serious or fatal^{[citation needed]} side effects in a newborn, including neonatal withdrawal syndrome, 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. However, the absolute dose excreted in milk is quite low, and tramadol is generally considered to be acceptable for use in breastfeeding mothers.

Dependency

Physical dependence and withdrawal

Tramadol is associated with the development of a physical dependence and a withdrawal syndrome. Tramadol causes typical opiate-like withdrawal symptoms as well as atypical withdrawal symptoms including seizures. The atypical withdrawal effects are probably related to tramadol’s effect on serotonin and norepinephrin reuptake. Symptoms may include anxiety, anguish, pins and needles, sweating, and palpitations. It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and when the time comes to discontinue their tramadol, to do so gradually over a period of time which will vary according to the individual patient and dose and length of time on the drug.

Psychological dependence and drug misuse

Some controversy exists regarding the dependence/addiction liability of tramadol. 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. They offer the theory that since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence.

Studies into the dependence liability of tramadol show that patients are no more likely to abuse the drug than normal NSAIDs. Despite these claims, it is apparent in community practice that dependence to this agent may occur, but in higher doses and long-term usage.^[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, rather than as a Schedule 8 Controlled Drug like opioids (Rossi, 2004). Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike opioid analgesics. Nevertheless, the prescribing information for Ultram warns that tramadol “may induce psychological and physical dependence of the morphine-type”. A controlled study that compared different medications found “the percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the dependency algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone”. This means that the abuse liability of tramadol was almost the same as that of normal NSAIDs, such as ibuprofen.

However, due to the possibility of convulsions at high doses, recreational use is very dangerous. Tramadol can however, via agonism of μ opioid receptors, produce effects similar to those of other opioids (e.g., morphine or hydrocodone), although not nearly as intense due to tramadol’s much lower affinity for the receptor. However, the metabolite M1 is produced after demethylation of the drug in the liver. The M1 metabolite has an estimated 200x greater affinity for the μ1, and μ2 opioid receptors. In addition to acting as an opioid, tramadol is also a very weak but rapidly acting serotonin-norepinephrine reuptake inhibitor. Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates which could deter abuse to some extent. Tramadol can help alleviate withdrawal symptoms from opiates, and it is much easier to lower the quantity of its usage, compared with opiates such as hydrocodone and oxycodone. It may also have large effect on sleeping patterns. High doses may prevent sleeping.

Animal treatment

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 monoamine 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 Deprenyl or any other psychoactive ingredient such as: serotonin reuptake inhibitors, 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 a starting dosage of 1-2 mg/kg twice a day will be useful for pain management. Cats are administered 2-4 mg/kg twice a day.

Legal status

Unlike most opioids, Tramadol is not considered a controlled substance in many countries (the US and Australia, among others), and is available with a normal prescription. Tramadol is available over the counter without prescription in a few countries. Sweden has, as of May 2008, 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. As of December 5th, 2008, Kentucky has classified Tramadol as a C-IV controlled substance.  Tramadol is sometimes mistakenly classified as an opioid analgesic, because of its agonist activity at the μ-opioid receptor, however, chemically it is not related to opioids.

Proprietary preparations

Grünenthal, which still owns the patent to tramadol, has cross-licensed the agent to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:

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January 20th, 2009

Alprazolam
Systematic (IUPAC) name
8-chloro-1-methyl-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Identifiers
CAS number	28981-97-7
ATC code	N05BA12
PubChem	2118
DrugBank	APRD00280
ChemSpider	2034
Chemical data
Formula	C17H13ClN4
Mol. mass	308.765
Pharmacokinetic data
Bioavailability	80-90%
Metabolism	Hepatic, via Cytochrome P450 3A4
Half life	Immediate release: 11.2 hours;Extended release: 10.7-15.8 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D(US)
Legal status	Schedule IV(US)
Routes	Oral

Alprazolam

Alprazolam, also known under the trade names Xanax, Xanor and Niravam, is a short-acting drug of the benzodiazepine class used to treat moderate to severe anxiety disorders, panic attacks, and as an adjunctive treatment for anxiety associated with moderate depression. It is also available in an extended release form, Xanax XR. Both forms are now available generically. Alprazolam is potentially an addictive drug and long term use of alprazolam may cause a physical dependence to develop and benzodiazepine withdrawal syndrome to appear during discontinuation. In the USA alprazolam is the most commonly misused benzodiazepine and is a schedule IV controlled drug.

History

Alprazolam was first synthesized by Upjohn (now a part of Pfizer). Its patent (#3,987,052) was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. It was released in 1981. The first indication for which alprazolam was approved was panic disorder. Upjohn took this direction at the behest of a young psychiatrist David Sheehan. Sheehan’s suggestion was to use the confusion DSM-III created in the classification of anxiety disorders (a distinction had just been made in DSM-III between generalized anxiety disorder (GAD) and panic disorder). Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective. However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and well responding to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder will both cover new diagnostic territory and stress the unique potency of this drug. Sheehan describes that the first group of patients treated by alprazolam was so impressed by its action that they knew outright—this drug was going to be a hit. A few of those patients actually pooled their money and purchased stock in Upjohn. Several months later, when alprazolam was approved by the FDA, they sold out and made a profit.

Pharmacology

Alprazolam is a triazolobenzodiazepine, that is, a benzodiazepine with a triazolo-ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine site on the GABA_A and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA_A receptor is made up from 5 subunits out of a possible 19, and GABA_A receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to benzodiazepines.

Pharmacokinetics

Alprazolam is readily absorbed from the gastrointestinal tract with a bioavailability of 80–100%. The peak plasma concentration is achieved in 1-2 hours. Most of the drug is bound to plasma protein, mainly serum albumin. Alprazolam is hydroxylated in the liver to α-hydroxyalprazolam, which is also pharmacologically active but much less so than the parent compound. This and other metabolites are later excreted in urine as glucuronides. Some of the drug is also excreted in unchanged form. The elderly clear alprazolam more slowly than younger patients.

Indications

The main medical uses for alprazolam include:

• Alprazolam is FDA-approved for the short term treatment (up to 8 weeks) of panic disorder, with or without agoraphobia. Alprazolam is very effective in treating moderate to severe anxiety, essential tremor and panic attacks. Physicians who elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks use as tolerance to alprazolam’s effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation. However, long-term maintenance therapy on alprazolam is not unheard-of in the medical community, and, if a genuine therapeutic need exists, benefits must be weighed against risks.

• Alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety. Alprazolam should only very rarely be used for longer periods of time – the body becomes rapidly tolerant to the drug’s effects, which may translate to decreased efficacy.

• Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence for antidepressant treatment of clinical depression in outpatient settings, evidence for inpatients is lacking.  The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors. Other benzodiazepines are not known to have antidepressant activity.  Studies show that any antidepressant action of alprazolam is questionable and generally weak in comparison to antidepressant medications.  Conversely, whilst alprazolam in acute or short term treatment may have some antidepressant properties there is evidence that up to a third of long term users of alprazolam may develop depression. However, many physicians and practictioners prescribe a benzodiazepine (i.e. alprazolam, diazepam, etc.) in conjunction with an antidepressant not to augment such a medication, as may be done with methylphenidate, but to lessen the severity of common side effects associated with an antidepressant regiment (i.e. anxiety, insomnia, restlessness, etc.).

Availability

Alprazolam is available in English-speaking countries under the following brand names: Alprax, Alprox, Alzam, Anxirid, Apo-Alpraz, Azor, Calmax, Gerax, Kalma, Niravam, Novo-Alprazol, Nu-Alpraz, Xanax, Xanor, Zopax.

Side effects

Side effects of alprazolam may occur in patients and are more likely the higher the dosage taken. If signs of an allergic reaction occur such as hives, difficulty breathing, swelling of face, lips, tongue or throat occur medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear such as yellowing of the skin or eyes. Other side effects which may occur are as follows:

• euphoria
• drowsiness
• decreased inhibitions, no fear of danger (increased risk taking behavior)
• depressed mood with thoughts of suicide or self harm or elevated mood and confidence
• hallucinations
• agitation
• feeling dizziness, light headed or fainting
• urinating less than usual or not at all
• headache, fatigue, joint pain and unusual weakness (flu like symptoms)
• speech problems,
• Short term memory loss and impairment of memory functions
• anterograde amnesia and concentration problems
• changes in appetite (including changes in weight)
• blurred vision, unsteadiness and clumsiness (impaired coordination and balance)
• constipation, diarrhea, nausea and vomiting
• decreased or increased sex drive
• dry mouth or, more likely, increased salivation
• sweating
• increase in appetite
• skin inflammation
• Aggression
• Mania

 Paradoxical side effects

Paradoxical side effects occasionally occur. Severe paradoxical effects such as seizures only rarely occur.

• hyperactivity
• nervousness
• restlessness
• sleeplessness
• muscle twitching
• tremor
• seizure (convulsions)

Physical dependence and withdrawal

See also: Benzodiazepine withdrawal syndrome

Alprazolam and other benzodiazepines cause the development of a physical dependence, tolerance and benzodiazepine withdrawal symptoms during dose reduction or cessation of therapy after long-term treatment.  When a patient discontinues use, they may experience the symptoms they had before taking medication but in an exaggerated form. This is known as rebound withdrawal. Symptoms may also be accompanied by other reactions including changes in mood, anxiety, or sleep. Severe rebound anxiety is usually a result of abrupt or over rapid discontinuation of this medication; patients who taper off slowly are less likely to experience these symptoms. Physical dependence is the major limiting factor against long-term use of alprazolam and other benzodiazepines. Discontinuation should be done gradually over a period of months (or even up to a year) to avoid serious withdrawal symptoms such as agitation, panic attacks, rebound anxiety, muscle cramps and seizures. Faster withdrawals are not recommended. If faster withdrawals are required eg for problematic substance misusers then it should be done in a hospital environment as an inpatient. Some patients on alprazolam (Xanax) may benefit from a substitution with a benzodiazepine equivalent dose of another benzodiazepine drug such as diazepam (Valium) or chlordiazepoxide (Librium) as these drugs remain in the bloodstream longer and therefore have less potential for misuse and the long half life and lower potency dose tablets available for diazepam and chlordiazepoxide allow for a smoother more gradual reducing withdrawal program with less intense withdrawal symptoms. There is a higher chance of withdrawal symptoms if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to wean itself off the drug.

If a consumer of the drug feels the need to end treatment with alprazolam, they should consult their doctor/physician before discontinuing medication. Some immediate symptoms of alprazolam withdrawal include:

Common Withdrawal Symptoms

• A rapid heartbeat (Tachycardia)
• Depression
• Dry mouth/chapped lips
• Temporary inability to stop talking/moving
• Mental sensitivity
• Strong loss of appetite
• Extreme Insomnia
• Anxiety
• Dizziness
• Minor tremors

Possible/Less Common Withdrawal Symptoms

• Nausea, cramps, vomiting, or diarrhea
• Panic attacks
• Mood swings
• Heart palpitations
• Hallucinations
• Memory los
• Seizure
• Feve

Patients treated with alprazolam or other benzodiazepines for generalized anxiety disorder were found (when abruptly discontinuing their medication) to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms

Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety. Other withdrawal effects reported from discontinuing alprazolam therapy include homicidal ideation, rage reactions, hyperalertness, increased nightmares and intrusive thoughts.  Grand mal seizures have occurred after abrupt withdrawal after only short term use. Therefore even short term users of alprazolam should taper off of their medication slowly and carefully to avoid serious withdrawal effects including seizures.

After 8–9 weeks of alprazolam taken at a fixed prescribed dose, the following symptoms have been found to occur during abrupt discontinuation: dysphoric mood, fatigue, low energy, confusion, and elevated systolic blood pressure, severe anxiety.

Alprazolam should never be abruptly discontinued if taken regularly for any length of time because severe withdrawal symptoms may occur. Severe psychosis and seizures have been reported in the medical literature from abrupt alprazolam withdrawal, and one death occurred from withdrawal-related seizures after gradual dose reduction.

The benzodiazepines diazepam (Valium) and oxazepam (Seresta) were found to produce less severe withdrawal symptoms than alprazolam (Xanax) or lorazepam (Temesta/Ativan). Alprazolam has an exceptional history insofar soon after its introduction a large number of case reports were published in the medical literature of severe withdrawal symptoms related case reports of withdrawal psychoses, seizures and intense rebound anxiety upon discontinuation of alprazolam. In the United States a survey of physicians showed that 84% of physicians reported alprazolam as being extremely problematic in terms of the severity and prolonged nature of the benzodiazepine withdrawal syndrome after discontinuation. Factors which determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal syndrome experienced during dose reduction of alprazolam include:

• dosage
• length of use
• frequency of dosing
• method of withdrawal
• personality characteristics of the individual
• previous use of cross dependent/cross tolerant drugs (alcohol or other sedative hypnotic drugs)
• current use of cross dependent/cross tolerant drugs (alcohol or other sedative hypnotic drugs)
• Use of short-acting high potency benzodiazepines for example alprazolam or lorazepam

Special precautions

Like all central nervous system depressants, including alcohol, alprazolam in doses of 0.5 mg and above can cause significant deterioration in alertness, combined with increased feelings of sleepiness. People driving or conducting activities which require vigilance should exercise caution in using alprazolam or any other depressant.

Contraindications

Use of alprazolam should be avoided, or carefully monitored by medical professionals, in individuals with the following conditions:

• Myasthenia gravis
• Acute narrow-angle glaucoma
• Severe liver deficiencies (e.g., cirrhosis)
• Severe sleep apnea
• Pre-existing respiratory depression
• Marked neuromuscular respiratory weakness including unstable myasthenia gravis
• Acute pulmonary insufficiency
• Chronic psychosis
• Hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class
• Borderline personality disorder (may induce suicidality and dyscontrol),

Pregnancy

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam. If one is currently planning to become pregnant, one should discuss this and all medicines with their obstetrician or other doctor.

Teratogenicity classification

Marked Pregnancy Category D by the U.S. FDA.

Effects on the fetus

It should be considered that the child born of a mother who is receiving benzodiazepines may be at risk of developing withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

Nursing mothers (neonates)

Benzodiazepines, including alprazolam are known to be excreted in human milk. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who use alprazolam.

Geriatric use

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side effects, especially loss of coordination and drowsiness.

Overdose

Overdoses can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Alprazolam (Xanax) overdose reflect the central nervous system depression of the brain and may include one or more of the following symptoms:

• Somnolence (difficulty staying awake)
• Mental confusion
• Hypotension
• Impaired motor functions
  • Impaired or absent reflexes
  • Muscle weakness
  • Impaired balance
  • Dizziness
• Fainting
• Hypoventilation (Respiratory Depression)
• Coma
• Death

About 50% of the cases of death involving alprazolam were attributed to combined drug toxicity of alprazolam and another drug, most often cocaine and methadone. Only 1% of such deaths was attributed to alprazolam alone. Alprazolam is significantly more toxic in overdose than other benzodiazepines.

  Recreational misuse   

Alprazolam, like all benzodiazepines, has the potential for abuse. Alprazolam itself is highly addictive and has a high potential for abuse. Most alprazolam abusers “are generally but not entirely limited to patients involved in a polydrug use pattern”Dose escalation is not typically a characteristic of long-term prescribed alprazolam

Injection of alprazolam is considered especially dangerous by medical professionals because, when crushed in water it will not fully dissolve (40µg/ml of H₂O at pH 7, and 12 mg/mL at pH 1.2 per 1mg of alprazolam), potentially causing severe damage to arteries if not filtered properly. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, has the potential to cause a serious, and potentially fatal overdose. Alprazolam may also be insufflated; clinical testing indicates potent activity through insufflation yet some sources indicate sublingual activity is greater.

Long term daily use of high or even low doses may totally eliminate the euphoric properties of the drug due to drug tolerance, leaving the user the desire to take it to only delay withdrawal symptoms or because of a “placebo” euphoric effect that is actually not due to the drug itself but due to psychological conditioning. Alprazolam is sometimes used with other recreational drugs to relieve the panic or distress of dysphoric reactions to psychedelics such as LSD and also to promote sleep in the “come-down” period following use of recreational drugs with stimulant or insomniac properties (such as LSD, cocaine, amphetamines, DXM, and MDMA along with the related amphetamines). It is also often used in conjunction with marijuana or heroin to potentiate the relaxing effect.

A large scale nation wide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines

 Patients at a high risk for abuse and dependence

At a particularly high risk for misuse, abuse, and dependence are polydrug abusers (someone who already uses at least one substance in a recreational context). However, the following can also indicate potential problems in the future:

• Patients with a history of alcoholism (including a family history of alcoholism) or drug abuse and/or dependence
• Patients with borderline personality disorder

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence because it may cause addiction. Discontinue therapy if any of these signs are noted, if a physical dependence has developed therapy will need to be discontinued gradually. Long-term therapy in these patients is not recommended, unless the net benefit to the patient outweighs the net risk.

Legal status

In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration. Under the UK drug misuse classification system benzodiazepines are class C drugs. Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.

See also

Food and drug interactions

 The effect of drinking grapefruit juice or consuming grapefruit while using alprazolam is not certain. Some web sites suggest that it increases blood concentrations by inhibiting the intestinal metabolism. However, there is a published paper, which suggests that the effect are in fact negligible because the effect on the inhibition of the CYP3A4 enzyme did not correlate, in a statistically significant manner, to the increase of blood plasma concentrations of alprazolam due to alprazolam’s high bioavailability.

Cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene and ritonavir all interact with alprazolam leading to a delayed clearance of alprazolam which may result in excessive accumulation of alprazolam.

Oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation^.

Alcohol is an important interaction. Alcohol and benzodiazepines such as alprazolam taken in combination have a synergistic effect on one another which can cause severe sedation, behavioral changes and intoxication. The more alcohol and alprazolam taken the worse the interaction.

Posted in Medical products | 8 Comments »

January 20th, 2009

Online phаrmаcy

Since аbout the yeаr 2000, hundreds of online phаrmаcies hаve begun operаting over the internet. Mаny such phаrmаcies аre, in some wаys, similаr to community phаrmаcies; the primаry difference is the method by which the medicаtions аre requested аnd received. Some customers consider this to be more convenient thаn trаveling to а community drugstore. While mаny internet phаrmаcies sell prescription drugs only with а prescription, some do not require а pre-written prescription. In some countries, this is becаuse prescriptions аre not required. Some customers order drugs from such phаrmаcies to аvoid the inconvenience of visiting а doctor or to obtаin medicаtions which their doctors were unwilling to prescribe. Mаny of these websites employ their own in house physiciаns to review the medicаtion request аnd write а prescription аccordingly. Some websites offer medicаtions without а prescription or а doctor review. This prаctice hаs been criticized аs potentiаlly dаngerous, especiаlly by those who feel thаt only doctors cаn reliаbly аssess contrаindicаtions, risk/benefit rаtios, аnd the suitаbility of а medicаtion for а specific individuаl.  Phаrmаcies offering medicаtion without а prescription аnd doctor review or supervision аre sometimes frаudulent. In the United Stаtes, there hаs been а push to legаlize importаtion of medicаtions from Cаnаdа аnd severаl Europeаn countries, in order to reduce consumer costs. аlthough importаtion of prescription medicаtion usuаlly violаtes Food аnd Drug аdministrаtion (FDа) regulаtions аnd federаl lаws, enforcement is generаlly tаrgeted аt internаtionаl drug suppliers, rаther thаn consumers. Often аmericаns purchаse lower-cost foreign drugs by driving to Cаnаdiаn or Mexicаn phаrmаcies, buying their medicаtions when trаveling аbroаd on vаcаtion, or, buying from foreign phаrmаcies thаt ship their orders viа mаil.

Internаtionаl consumers

     Internаtionаl consumers often purchаse drugs online from online phаrmаcies in their own countries, or those locаted in other nаtions such аs Indiа, Spаin, Pаkistаn аnd the Philippines. Some of these phаrmаcies require prescriptions, while others do not. Of those which do not require prescriptions, some do аsk the customer to fill in а heаlth questionnаire with their order. Drugs аvаilаble online аre often produced by well-known mаnufаcturers such аs Pfizer, Wyeth, Roche, аnd generic Indiаn drugmаkers Ciplа аnd Rаnbаxy аnd Tevа Phаrmаceuticаl Industries of Isrаel. It is а fаirly common prаctice for North аmericаn аnd Europeаn visitors to countries like Thаilаnd, Indiа аnd South аfricа to purchаse аnd bring home аffordаble medicаtions for themselves, fаmily members аnd/or friends. Sаvings cаn be significаnt, often exceeding 80 percent compаred to the sаme medicаtions аvаilаble in their home countries. Trаvellers mаy аvoid possible difficulties inherent to physicаlly going through customs with their medicаtion purchаses by mаiling the drugs to their home so they receive them upon their return.

U.S. consumers

     To sаve money, millions of uninsured аnd underinsured U.S. consumers purchаse drugs from online phаrmаcies in Cаnаdа, Indiа, the UK аnd other countries аnd receive their purchаses by mаil. Especiаlly for uninsured аmericаns tаking prescription drugs for chronic heаlth conditions, а mаjor аttrаction of online phаrmаcies аbroаd is thаt neаrly every country, except the U.S., controls its drug prices. Shoppers cаn eаsily obtаin 50 to 80 percent or more sаvings аt foreign phаrmаcies, in compаrison to US prices. Very rаrely аre these orders investigаted becаuse U.S. аuthorities аre much more worried аbout controlling illegаl phаrmаcies in the U.S., not consumers themselves. In fаct, the Wаshington Post reported thаt “.. millions of аmericаns hаve turned to Mexico аnd other countries in seаrch of bаrgаin drugs…U.S. Customs estimаtes 10 million U.S. citizens bring in medicаtions аt lаnd borders eаch yeаr. аn аdditionаl 2 million pаckаges of phаrmаceuticаls аrrive аnnuаlly by internаtionаl mаil from Thаilаnd, Indiа, South аfricа аnd other points. Still more pаckаges come from online phаrmаcies in Cаnаdа.” Until аbout 2005, аmericаn consumers looking аbroаd most commonly turned to Cаnаdiаn phаrmаcies for аffordаble medicаtions.  Todаy, mаny consumers heаd to online phаrmаcies in Indiа, South аfricа аnd other countries where drug prices аre often lower thаn in Cаnаdа. аmong well-respected online phаrmаcies serving US pаtients аre InternаtionаlDrugMаrt.com аnd IsrаMeds.com. а report in the journаl Clinicаl Therаpeutics found thаt U.S. consumers fаce а risk of getting counterfeit drugs becаuse of the rising Internet sаles of drugs, projected to reаch $75 billion by 2010.
Overseаs online phаrmаcies аnd U.S. lаw

Legality and risks of purchasing drugs online depend on the specific kind and amount of drug being purchased.

• • While rarely enforced, it is usually illegal to purchase controlled substances from an overseas pharmacy. Generally speaking, a person purchasing a controlled substance from such a pharmacy may be violating two federal laws which can carry stiff penalties. The act of importation of the drug from overseas violates 21 USC, Section 952 (up to 5 years in prison and $250,000 fine for importation of non-narcotic Schedule III, IV, or V drugs; possibly more for narcotics and Schedule I and II drugs). The act of simple possession of a controlled substance without a valid prescription violates 21 USC, Section 844 (up to 1 year in prison and $1,000 fine). Note that FDA does not recognize online prescriptions; in order for the prescription to be valid, there has to be a face-to-face relationship between the patient and the health care professional prescribing the drug. What exactly constitutes a “face-to-face” relationship is considered by many online pharmacies to be a subjective definition which would allow them to operate as an adjunct to the patient’s own physician if the patient submits medical records documenting a condition for which the requested medication is deemed appropriate for treatment. Sections 956 and 1301 provide exemptions for travellers who bring small quantities of controlled substances in or out of the country in person, but these exemptions do not cover delivery via a mail carrier.
  • Importation of any prescription drug (not necessarily a controlled substance) violates 21 USC, Section 301(aa), unless the following conditions are met (as listed in Section 804):
    1. The drug is imported from Canada, from a seller registered with the Secretary (i.e. with FDA);
    2. The drug is imported from a licensed pharmacy for personal use by an individual, not for resale, in quantities that do not exceed a 90-day supply;
    3. The drug is accompanied by a copy of a valid prescription;
    4. The drug is a prescription drug approved by the Secretary;
    5. The drug is in the form of a final finished dosage that was manufactured in an establishment registered under section 510; and
    6. The drug is imported under such other conditions as the Secretary determines to be necessary to ensure public safety.
  • The law further specifies that enforcement should be focused on cases in which the importation by an individual poses a significant threat to public health, and discretion should be exercised to permit individuals to make such importations in circumstances in which the prescription drug or device imported does not appear to present an unreasonable risk to the individual.
  • According to Department of Homeland Security Appropriations Act, Section, Customs and Border Patrol are not allowed to prevent people from importing FDA-approved prescription drugs. Although originally the law was worded to cover all prescription drugs, countries of origin, and methods of delivery, its final edition specifies that it only applies to importation from Canada, and to “…individuals transporting on their person a personal-use quantity of the prescription drug, not to exceed a 90-day supply”. Controlled substances are also explicitly excluded. Therefore, it does not disallow Customs to screen and intercept drugs sent by mail.
  • It is also technically illegal to import “non-approved” drugs (21 USC sections 331(d) and 355(a)); however, FDA policies suggest that, under certain circumstances, the patients may be allowed to keep these drugs.
  • Individual U.S. states may implement their own laws regulating importation, possession, and trafficking in prescription drugs and/or controlled substances.
  • For several years, the states of Nevada, Minnesota, Illinois and Wisconsin have run official state programs to help their residents order lower-cost drugs from abroad to save money.
  • Most online pharmacies worldwide will send consumers a free replacement order if their order is not received for any reason, including customs seizure (some do require the customer to submit a copy of the seizure letter they received from customs, in order to prevent fraudulent claims of non-receipt). Normally, consumers should wait about 30 days after placing their order before considering this option. When considering an order, a prospective customer should read the rules regarding reships on the pharmacy’s website.

  Enforcement

  Enforcement of the laws listed in the previous section can be difficult (and in some cases purposely lax), as evidenced by the many profitable online pharmacies worldwide. Among other reasons, strict drug law enforcement is politically unpopular because many customers of online pharmacies are seniors and the uninsured who cannot afford to buy their prescription drugs in the United States.

  • Any package containing prescription drugs may, in principle, be seized by customs. The package may be held and eventually returned to the sender if the addressee does not respond and provide proof that they are allowed to receive these drugs (e.g., a valid prescription). (Sample package detention notification letter) In practice, the number of packages containing prescription drugs sent to United States on a daily basis far exceeds Customs’ capabilities to inspect them.  In the past, packages often passed through customs even if they were not sent from Canada or otherwise didn’t meet the requirements of section 804 of 21 USC. Until recently, about 5 percent of prescription drug packages sent from Canada were being seized.
  • At the present time, U.S. customs does not seize packages from Canada.
  • DEA and FDA generally do not target consumers unless drugs are imported in large quantities (suggesting intent to distribute) or represent a perceived danger to public health (opiates, amphetamines).
  • Rarely, drug importation laws are enforced on the local level. For example, in June 2005 in Baton Rouge, Louisiana, a number of customers of online pharmacies were arrested by local law enforcement officers and charged with possession of a controlled substance without prescription.

Posted in Medical products | 11 Comments »