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A detailed pharmacological S.W.O.T analysis of the hypnotic Triazolam.
Introduction
Triazolam (brand name Halcion) is thegeneric name of a sleep promoting drug used in patients that suffer frominsomnia. It is a member of the benzodiazepine (BZPs) family of drugs. Thisfamily includes amongst others; alprazolam (Xanax), diazepam (Valium),flurazepam (Dalmane), lorazepam (Ativan) clonazepam (Klonopin) (FDA,2003).
Benzodiazepines werefirst used 40 years ago and they were seen to be a breakthrough in the field,having fewer drawbacks than its predecessors. BZPs have a satisfactorily widesafety margin for overdoses, nominal pharmacokinetic drug interactions, and a goodlevel of tolerability, while maintaining effectiveness for a broad range ofconditions. Because of this, BZPs continue as widely prescribed drugs worldwide(Janicak, 1997, Greenblatt, 2000).
Existing uses of BZPs arediverse. Amongst the conditions treated are insomnia, mania, anxiety disorders(panic disorder, generalized anxiety, phobias, anxiety associated withobsessive compulsive disorder), catatonia, and behavior control in psychoticpatients, neuroleptic-induced side effects including akathisia, muscle spasms,seizures, and alcohol withdrawal (Wheatly, 1992).
Anxiety is thought to be the underlyingcause of insomnia, a condition where the brain is overly active.Gamma-aminobutyric acid (GABA), produced in the brain, is a substance whichinhibits nerves and countless activities of the brain. Triazolam and other BZPsaugment the effects of GABA and so reduce activity in the brain which promotessleep (Greenblatt, 2000 and 2004).
Triazolam was approved by the FDA in 1982. The product licenses for triazolam inBritain were suspended in October 1991 (FDA, 2003).
Pharmacology
The hypnoticpharmacokinetic profile of triazolam is very desirable. It has a very shortelimination half-life, is rapidly absorbed and peak plasma concentration (C(max)) is reached in 1.0 to 1.5 hours following oral administration (Kales,1986).
C (max) and area underthe plasma-concentration curve (AUC) increase in proportion to the dose, howeverthe time to peak plasma concentration, elimination half-life, and clearance areindependent of dose. The elimination half-life is 2.3 hours (range 1.7 to 3.0hours) (Bernstein, 1995).
Triazolam is metabolised bymeans of hepatic microsomal oxidation. The inactive, hydroxylated metabolitesare excreted mainly in the urine as conjugated glucuronides. The two primarymetabolites account for approximately 80% of the urinary excretion. Repetitive administrationof triazolam over 7 days does not lead to accumulation and does not alter therate of elimination (Jonas, 1992).
Pharmacokinetics in the elderly
People that are aged over 60 do notdemonstrate an altered elimination half-life, though peak plasma concentrationsare significantly increased. The kinetics of triazolam is significantlyprejudiced by age. Following single oral doses of 0.125 mg and 0.25 mg oftriazolam, C (max) and AUC were significantly higher and clearancesignificantly lower in elderly subjects than in younger one. Age, however, didnot influence the time to peak plasma levels and differences in eliminationhalf-life were diminutive (Greenblatt, 2004).
S.W.O.T analysis
Strengths
The effectiveness of triazolamhas been verified in many studies including Rickels et al, (1998) who affirmed thattriazolam caused significant and identical reduction of insomnia. Long found in1995 that in sleep laboratory studies of 1 to 21 days duration, triazolamreduced sleep latency, increased duration of sleep and decreased the number ofawakenings.
Triazolam has a highly advantageousclinical outline; it is very easy to deliver as it is available in oralcapsule. Patients are able to self-administer generally with no problems. It isfast acting, C (max) being reached in as little as one hour. The eliminationhalf-life and excretion rate is extremely swift; therefore it is removed fromthe system quickly, indicating there is negligible residual action in the body(Quarnstorm, 2004).
Triazolam has a high selectivity forthe cerebral GABAA benzodiazepine (BDZ)receptor complex, however the binding is weak. This is important because drugswith low selectivity have the ability to bind to other receptors and perhapscause undesirable effects in other areas of the body.
Cost is a factor which even thoughnot associated with safety of the drug, affects how often a clinicianprescribes. Triazolam is an effective and inexpensive drug; in 2005 the costfor a month's supply of the drug in the USA costs $3 (Oregan GUR, 2005) which is considerablecheaper than other comparable drugs.
Weaknesses
The study that Longperformed in 1995 highlighted the efficacy of triazolam but also demonstratedits weaknesses. He found that after 2 weeks of consecutive nightlyadministration, the drug's effect on total wake time is diminished, and thevalues in the final third of the night approach baseline. On the first orsecond night after drug discontinuance, total sleep, and proportion of timespent sleeping frequently were significantly less, and sleep latency drasticallyincreased when evaluated against baseline nights, an effect known as"rebound" insomnia.
The extent ofhypnotic effect and presence of unwanted effects may be subject to the alpha(distribution) and beta (elimination) half-lives of triazolam. Triazolam has ashort half-life which means, the drug and its metabolites will be excreted priorto ingestion of the next dose. Residual effects associated with sedation or CNSdepression are minimal or absent. During nightly use and for an extendedepisode, pharmacodynamic acceptance or adaptation to some effects of triazolammay develop (APA, 1990).
The drug hasa very brief elimination half-life; therefore it is possible that a deficiencyin relation to the receptor site could take place at some point in the intervalbetween each nightly use. This occurrence may account for the two clinicalfindings; Increased wakefulness during the last third of the night and theappearance of increased day-time anxiety, which were reported after severalweeks of nightly use of triazolam.
Triazolam can contributeto the results other drugs demonstrate that inhibit activity in the brain. Thisincludes alcohol, barbiturates, narcotics and some pharmacy antihistamines(e.g. Benadryl). Combining these drugs with triazolam may cause extreme sedation.When employed for indications other than insomnia, this sedation is often a drawbackand could place vulnerable patients such as the elderly at risk (APA, 1990).
Another undesirableeffect is that some drugs (e.g. itraconazole, erythromycin and fluconazole), and alsograpefruit juice (Lilja, 2000), can block the metabolism of triazolam from thebody. This raises triazolam levels and also causes excessive sedation. At theopposite end of the spectrum, drugs such as Phenytoin and rifampin increasethe rate of elimination of triazolam from the body and can initiate a loss oftriazolam's effectiveness.
Memory problems havebeen recognized in all BZPs and are especially problematic with triazolam. Thisis potentially frightening to patients and there are several lawsuits focusingon this in the USA, against clinicians who did not warn their patients of thispossibility (Rothschild, 1992).
When a drug interfereswith the usual inhibiting action of GABA within the central nervous system, thiscan lead to uncontrolled firing of impulses, resulting in the escape fromhigher cortical control. This means that behavior can be altered to a state ofdisinhibition. This can be a particular problem with the use of triazolam.
In the elderly who aretaking BZPs, falls and ataxia are of a particular concern. Those takingtriazolam are 1.5-3 times more likely to suffer a fall.
Opportunities
There is very little inthe way of opportunities for the development of triazolam. The levels ofefficacy and selectivity that it demonstrated are ideal. It is also cheap andeasy to deliver. Opportunities for progress with this drug centre around itspossible re-release to the worldwide market (Berstein, 1995).
In 1979, the safety of triazolamwas first queried when van der Kroef reported a syndrome that includeddepression, amnesia, hallucinations, and anxiety with its use. Many othersafety concerns followed this. In 1992 the Food and Drug Administration (FDA) decreasedthe dose recommended in the labeling down to 0.25 mg for adults and 0.125 mgfor the geriatric population. These lower doses were not included in thestudies performed during the original FDA approval process. The change raisesthe question of if there is adequate data to support the recommendation andwhether the minimum effective dose has been established.
To try toanswer these dose-related efficacy questions and to evaluate the value of thedata the FDA based its decision that triazolam was effective at the lower doseson, an evaluation and reanalysis of the data was performed using a statisticalmethod different from that used by FDA, the report was inconclusive and needsfurther research. (Marticello, 1992);
There is theprospect that triazolam could be a useful drug in other fields. Other drugswhich have been found to be problematic in their original field have gone on tobe very successful in other areas. An example of this is thalidomide; thecontroversy surrounding this drug has been well documented for its initial usein the 1940s and 1950s, used to cure morning sickness, but it is now apotential candidate anti-cancer drug.
Threats
Triazolam's safety has beenquestionable. In 1991, as a result of a US court case, the UK's Committee onSafety of Medicines (CSM) became aware that in the product license applicationfor triazolam, there were a number of omissions of adverse events.
Studies were conducted in US volunteersin 1972 using a 1 mg dose of triazolam. Pharmacia & Upjohn (manufacturer oftriazolam), provided the CSM with the original clinical record forms from thestudy for review. The CSM reappraisal of this protocol and adverse drugreaction records from the UK and US led to the conclusion: ". . . thattriazolam is associated with an inadequate margin of safety in relation to doseand that its risks outweigh its benefits in relation to otherbenzodiazepines." (CSM, 1992)
An FDA memo from 1994 exposedthe fact that 30 percent of the serious adverse drug reactions seen in thestudy subjects had not been reported to the FDA before the drug's approval in theUS. Marketing approval for triazolam was in the end, withdrawn in the UK,Brazil, Argentina, Norway, and Denmark.
There are risksassociated with:
Dependency: after anumber of weeks of use, physical dependency can arise and frequently becomes obviouswhen attempting to end extended periods of use. With rapid withdrawal, patientssuffer a swift relapse of original symptoms often with inflated intensity(rebound) and accompanied by new symptoms (withdrawal) (Jonas, 1992).
The CSM inthe UK concluded that the risks linked with triazolam use prevail over thebenefits and that this agent should be avoided, particularly in the elderly(CSM, 1992).
Conclusion
Triazolam has achievednotoriety because of reports that it causes behavioral disturbances, includingpsychosis and violent behavior (Wheatley, 1992). However, the doses involved(over 1 mg) were twice the usual maximum dose currently prescribed (Kales,1986). These effects remain controversial because two meta-analyses of studiescomparing triazolam with other benzodiazepines have failed to show anydifference in behavioral effects (Jonas, 1982, Kales, 1986).
This was also noted by Jonas in 1992. The efficacy,safety, and performance of triazolam was evaluated against other shorter-actinghypnotics acting on the GABA receptor (zopiclone, zolpidem, midazolam,brotizolam, temazepam, lormetazepam, and loprazolam).
Two broad findings cameforward. Excitement and violence were not demonstrated for any of the hypnoticagents, including triazolam. These are generally viewed as "serious"central nervous system side effects. Additional central nervous system sideeffects, e.g. depression and irritability, were demonstrated in equal numbersfor all the hypnotics appraised.
Rebound insomnia, commonlyreported with most of these hypnotics, was brief and not clinicallysignificant. Early morning insomnia was noted on one occasion and was notclinically significant. In contrast to claims that triazolam is anxiogenic,anxiety was not a large finding within the cohort.
Secondly, a notablecomparison was established among all the agents in terms of efficacy, sideeffects, and performance related effects. Claims have been made suggesting differences;evaluation of the study did not demonstrate this. Therefore difference in chemicalstructures does not necessarily predict a difference in clinical profiles whendrugs share a similar mechanism of action (Jonas, 1992, Kamien, 1994)).
Triazolem remainslicensed in the USA. The American Public Health Research Group (APHRG) has saidthat Halcion is too dangerous to use and we advise anyone using it to asktheir doctor to help them slowly withdraw from the drug it is addicting orswitch to a safer sleeping pill.
The market, as well asthe U.K. government, has also spoken loudly and clearly about the drug. Sales,measured by retail prescriptions filled per year, have plummeted from a peak of11 million prescriptions a year in 1988 to 1.8 million in 1996, a drop of 84%(Peart, 1998).
Huge numbers of studiespoint to the fact that triazolam is not a safe and effective drug. Halcion isused primarily to combat insomnia on a very short-term basis. When taken forover two weeks, Halcion usually loses its effectiveness. There are a wide rangeof alternative drugs available to treat insomnia and anxiety disorders which couldbe used in preference to triazolem (Kamien, 1994).
Conversely, the drug ischeap and very effective in the short term. More studies are required todetermine its safety, both in the short and long term. There appears to be anequal opinion for and against it. It is doubtful that triazolam would begranted a license today due to the negative findings in studies and the hugedebate surrounding the drug, however if its safety could be finally determinedthen it would be a useful agent. Its use in other directions should also beinvestigated before deciding the future fate of the drug. Data from the USAwould be a valuable asset in the drugs future as it is still widely used there(Barbera, 2005).
References
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