Drug Abuse & Misuse

Sedative-Hypnotics“Benzodiazepines”

Dr. Asra Hameed Pharm.D (JUW) asra_hameed1@hotmail.com

Sedative-Hypnotics

• Sedative-hypnotics are drugs that depress or slow down the body's functions. 

• Often these drugs are referred to as tranquilizers and sleeping pills or sometimes just as sedatives. 

• Their effects range from calming down anxious people to promoting sleep. 

• Both tranquilizers and sleeping pills can have either effect, depending on how much is taken.

• Barbiturates and benzodiazepines are the two major categories of sedative-hypnotic. 

Benzodiazepines

• A benzodiazepine (sometimes collectively benzo often abbreviated " BZD ") is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring.

• Benzodiazepines act by enhancing presynaptic/postsynaptic inhibition through a specific BZD receptor which is an integral part of the GABA A receptor- Cl channel complex.

• Benzodiazepines are basically sedatives drugs that have been prescribed around the world over several decades for a range of indications including:

Anxiolytic (relief of anxiety) Hypnotic (promotion of sleep) Myorelaxant (muscle relaxation) Anticonvulsant (control fits convulsions) Amnesia (sedation for surgical procedures)

Chemical structures of benzodiazepines

Pharmacokinetic Properties Of Some Benzodiazepines & Newer Hypnotic In Human

Drug peak blood Elimination Comment level(hr) half-life(hr)Alprazolam 1-2 12-15 rapid oral absorbtion

Chlordiazpoxide 2-4 15-40 active metabolites;erratic bioavailibility from IM injection

Clorazepate 1-2 50-100 prodrug;hydrolyzed to active from in stomach

Diazepam 1-2 20-80 active metabolites;erratic bioavailibility from IM injection

Eszopiclone 1 6 minor active metabolites

Flurazepam 1-2 40-100 active metabolites with long half-life

Lorazepam 1-6 10-20 no active metabolites

Oxazepam 2-4 10-20 no active metabolites

Temazepam 2-3 10-20 slow oral absorbtion

Triazolam 1 2-3 rapid onset;short duration of actoin

Zaleplon <1 1-2 metabolized via aldehyde dehydrogenase

Zolpidem 1-3 1.5-3.5 no active metabolites

BENZODIAZEPINE ABUSE

Key points

• Benzodiazepine abuse is a growing problem and carries serious risks to health and society.

• Benzodiazepines are commonly used by polydrug abusers, alcoholics and sometimes as primary recreational drugs.

• People who abuse benzodiazepines often take very large doses orally, by injection or by snorting.

• Benzodiazepine use leads to dependence and a withdrawal syndrome which may include convulsions and psychosis.

• Further research is needed on the optimal short-term and long-term management of benzodiazepine abuse.

• The primary source of illicit benzodiazepines is from doctors' prescriptions.

BENZODIAZEPINE ABUSE

Benzodiazepines are consumed by two main populations with different characteristics:

(1) low-dose prescribed benzodiazepine users and (2) high-dose, non-prescribed benzodiazepine abusers

It has been claimed that benzodiazepine abuse is 'of little or no consequence' in the huge population of prescribed benzodiazepine users.However, a proportion of prescribed users do escalate dosage, take the drugs for hedonic effects and enter into the illicit drug scene.It is important to remember that substance misuse can occur across a wide spectrum of ages and not to allow prejudice to hinder older people's diagnosis and treatment.

Why abuse benzodiazepines?

• The most common reason given by polydrug abusers for taking benzodiazepines is that they enhance and often prolong the 'high' obtained from other drugs including heroin, other opioids, cocaine and amphetamines. Benzodiazepines are mainly taken along with the primary drug, but sometimes used alone as an alternative or in times of shortage.

• Second, benzodiazepines alleviate withdrawal effects, including anxiety and insomnia, when supplies of other drugs are limited. Users of stimulants including cocaine, amphetamines and Ecstasy also take benzodiazepines as 'downers' to overcome the effects of their 'uppers' and to combat hangover effects.

• In alcoholics, benzodiazepines are used partly to alleviate the anxiety associated with chronic alcohol use, but also because the mixture of alcohol and benzodiazepines produces a hedonic effect.

• Finally, benzodiazepines, when taken alone in high doses and particularly when injected, can themselves provide a 'kick'.

Why abuse benzodiazepines?

• Although benzodiazepines in therapeutic doses have been claimed to have little abuse potential compared with other drugs of abuse, their abuse liability may vary along the dose-response curve, becoming greater at doses above the therapeutic range.

• Diazepam, alprazolam, lorazepam and triazolam have all been shown in clinical laboratory studies to possess abuse liability.

• Alprazolam 1mg was comparable with 10mg d-amphetamine in scores for 'elation' and 'abuse potential' in experienced but non-dependent users.

• 'High' ratings for oxazepam and chlordiazepoxide were lower than for other benzodiazepines.

• The non-benzodiazepine hypnotic zolpidem produced 'drug liking' scores similar to triazolam; this drug and the similar non-benzodiazepine hypnotic zopiclone may also have abuse potential.

Which benzodiazepines are abused?

• Nearly all the available benzodiazepines have been abused. In general, those which enter the brain rapidly (e.g. diazepam) are preferred to those which are absorbed more slowly (e.g. oxazepam).

• However, preferred drugs vary between countries and over time depending on their availability and reputation in the illicit drug world.

Generic name Brand name (UK)

Alprazolam Xanax

Bromazepam Lexotan

Chlordiazepoxide Librium

Diazepam Valium

Flunitrazepam Rohypnol

Flurazepam Dalmane

Ketazolam1 Anxon

Lorazepam Ativan

Medazepam1 Nobrium

Nitrazepam Mogadon

Oxazepam Serenid

Prazepam1 Centrax

Temazepam Normison, Euhypnos

Triazolam1 Halcion

(Zopiclone)2 Zimovane)

(Zolpidem)2 (Stilnoct)

Notes: 1No longer in British National Formulary. 2Non-benzodiazepine hypnotics with similar actions to benzodiazepines; may have abuse liability.

Routes of administration and dosage

• Benzodiazepines can be taken by mouth, inhaled as snuff or injected. The commonest practice is oral ingestion but, recently, novel forms of administration have been used.

• Intranasal 'snorting' of powdered flunitrazepam. • The main alternative to the oral route is intravenous injection.• Diazepam and other benzodiazepines have been injected but at present temazepam is mainly

involved. • Temazepam was the most commonly used and had been injected from preparations of capsules,

tablets and syrup. • Other injected benzodiazepines are diazepam, lorazepam, triazolam, nitrazepam and

chlordiazepoxide. • Attempts to discourage temazepam injections by substituting liquid with gel-filled capsules and

by introducing tablets and elixir appear to be unsuccessful since the gel can be warmed to a liquid consistency, the tablets can be dissolved in warm water and the elixir diluted to provide injectable solutions.

Sources of benzodiazepines

• Benzodiazepines are widely available on the Street and are cheap.

• A major source is from general practitioners' prescriptions. • Some users attend several practitioners using false names and

temporary patient status; others obtain supplies from friends or patients (often elderly people) who exaggerate their needs to their doctors and sell off the excess.

• Some children obtain them from prescriptions for their parents.• Benzodiazepines are also obtained by theft from health centres

or retail chemists, and large amounts have been stolen from pharmaceutical warehouses.

Health risks and social consequences

General Complications of IV use

Fatalities due to overdose (particularly in combination with opioids) Thrombophlebitis

Blackouts and memory loss Deep and superficial abscesses

Paranoia Deep vein thrombosis

Violence and criminal behaviour Pulmonary microembolism

Risk-taking sexual behaviour Rhabdomyolysis, tissue necrosis

Foetal and neonatal risks if taken in pregnancy

Gangrene, requiring amputation (usually due to inadvertent intra-arterial injection)

Dependence Hepatitis B and C

Withdrawal seizures HIV infection

Health risks and social consequences

• Benzodiazepines are generally believed to be safe in overdose, but deaths following self-poisoning do occur, even when the drugs are taken alone, and a fatal outcome from overdose is more likely with flurazepam and temazepam than with other benzodiazepines.

• Benzodiazepines also add to the respiratory depression caused by other drugs: the combination of temazepam with injected opioids (e.g. buprenorphine) is said to cause approximately 100 deaths a year in Glasgow alone.

• Benzodiazepine use increases the risk of road traffic accidents, especially when driving under the influence of higher doses.

Health risks and social consequences

• Mental disturbances caused by benzodiazepines include blackouts and memory loss, aggression, violence and chaotic behaviour associated with paranoia.

• The loss of judgement and amnesia caused by benzodiazepines may also be associated with high-risk sexual behaviour including casual sexual contacts and unprotected sexual activity which appears to be a particular feature of temazepam abusers.

• Cognitive impairment, including deficits in learning and memory and in sustained attention, has been shown in many studies of long-term benzodiazepine users, even at therapeutic dose levels, and may persist after benzodiazepine withdrawal.

• Risks of maternal use during pregnancy include foetal developmental abnormalities, 'floppy infant syndrome' and a neonatal benzodiazepine withdrawal syndrome.

• Regular use of benzodiazepines, especially in high doses, readily leads to physical dependence, evidenced by withdrawal symptoms on sudden cessation.

Dependence and withdrawal symptoms

• Feeling faint• Noise sensitivity• Light sensitivity• Peculiar taste• Pins and needles• Touch sensitivity• Sore eyes• Hallucinations• Smell sensitivity

• Depression• Shaking• Feeling unreal• Appetite loss• Muscle twitching• Memory loss• Motor impairment• Nausea• Muscle pains• Dizziness• Apparent movement of still

objects

Management of benzodiazepine withdrawal

• Withdrawal methods for long-term prescribed therapeutic dose benzodiazepine users are well established and consist mainly of slow dosage tapering over weeks or months in an outpatient setting, combined with psychological support.

• These methods are not entirely appropriate for high-dose benzodiazepine abusers.

• First, benzodiazepine abuse is often part of polydrug abuse and attention also has to be given to the primary drug.

• Second, a long period of outpatient dosage tapering is unlikely to be adhered to since additional benzodiazepines may be obtained illicitly.

• On the other hand, benzodiazepine abusers commonly use high doses and may be at particular risk of severe withdrawal symptoms including epileptic fits if the drugs are stopped abruptly.

• Therefore, a moderately rapid, controlled schedule of detoxification in an inpatient unit is preferable.

Management of benzodiazepine withdrawal

• The most common technique is substitution of a slowly eliminated benzodiazepine (usually diazepam) for the abused drug (commonly, a shorter acting drug such as temazepam) followed by dosage tapering over 2 or more weeks.

• Some workers have advocated the use of carbamazepine as an anticonvulsant in benzodiazepine withdrawal, though its ability to prevent other withdrawal symptoms is doubtful.

• A third method of detoxification recommended in some centres, particularly in the US, is phenobarbitone substitution.

Management of benzodiazepine withdrawal

• Longer term outpatient management of benzodiazepine abusers is problematic.

• Some centres have found benzodiazepines to be helpful in reducing overall illicit drug use and injecting, and, occasionally, benzodiazepine use may be adaptive, allowing the opiate abusers to manage on a smaller dose of methadone.

• However, the overwhelming advice is that it is generally inadvisable to prescribe benzodiazepines as maintenance treatment for drug misusers or alcoholics.

• A possible approach for opiate addicted patients who use benzodiazepines to increase the euphoriant effects of methadone is to alter the methadone treatment so that individuals feel less need for benzodiazepines.

Management of benzodiazepine withdrawal

• Unfortunately, in the present climate the rate of relapse after short-term benzodiazepine detoxification may be as high as it is with opiate detoxification (i.e. over 90 per cent after 1 year), and further experience is needed to establish the optimal long-term management.

• Meanwhile, efforts to reduce inappropriate prescribing of benzodiazepines both in general practice and in hospital may help to decrease the quantity of benzodiazepines at present spilling into the illicit drug market.

DIAZEPAM

Taking Diazepam for longer than 4 months, even with a prescription from a doctor, increases the likelihood of becoming addicted.

Understanding Diazepam Addiction

• Diazepam is an addictive benzodiazepine with longer-lasting effects than other drugs in its class.

• An addiction to Diazepam can progress quickly if the drug is used in a way not directed by a doctor.

• Over time, it is harder for a Diazepam abuser’s brain to function normally without the drug. Yet, some people addicted to Diazepam may not even realize they have a problem.

• One of the telltale symptoms of a Diazepam addiction is needing larger doses to feel the drug’s effects. Other signs of an addiction to Diazepam include:• Strong cravings for the drug• Isolation from family and friends• Continued use despite problems caused by the drug• Loss of interest in once enjoyable activities• Ignoring obligations

Understanding Diazepam Addiction

• Once a user has a tolerance to Diazepam’s effects, they could also have withdrawal symptoms if they stop taking it.

• Diazepam withdrawal can be dangerous and uncomfortable, which makes it hard to for addicted people to quit on their own.

• The symptoms of withdrawal are intense, and many people addicted to Diazepam need the drug to feel normal.

What Is Diazepam?

• Diazepam is most often prescribed to relieve anxiety, muscle spasms and seizures. It is also used to ease uncomfortable symptoms of alcohol withdrawal.

• Diazepam works by diminishing hyperactive brain function to relieve severe stress and anxiety. It is ingested orally in pill form and usually taken 1-4 times per day when prescribed by a doctor.

• Diazepam is a long-acting benzodiazepine.

Effects of a Diazepam and Reasons for Abuse

• While there are several reasons for Diazepam abuse, many of those abusing the drug don’t take it to get high. They take it to feel normal — to relieve stress and anxiety. People also abuse Diazepam because it helps them sleep. Diazepam produces a sense of intense calm and euphoria, especially in higher doses.

• Many people mistakenly think that because it is legal, Diazepam must be safe and less addictive than street drugs like heroin or cocaine. Due in part to these misconceptions, many people have accidentally overdosed.

The Dangers of Diazepam

• Many people underestimate the addictive potential of Diazepam because it’s prescribed by a doctor. Even fewer people seem to be aware of the dangers of the drug. Diazepam can lead to convulsions and coma in heavy users. Studies have also shown that people on Diazepam have an increased risk of motor vehicle accidents. And when a user stops taking the drug, Diazepam withdrawal can be deadly.

• Diazepam is especially dangerous when mixed with other central nervous system depressants like alcohol and opioid painkillers. The sedative qualities of each substance taken together are amplified. This can depress breathing or heart rates to the point of failure.

Some signs of a Diazepam overdose include:

Bluish lips

Double vision

Drowsiness

Trouble breathing

Weakness

Uncoordinated movement

Some signs that may indicate Diazepam abuse include:

Slurred speech

Impaired coordination

Dilated pupils

Changes in appetite

Uncharacteristic sadness or irritability

Shaking (from withdrawal)

Diazepam Withdrawal

• Once a physical dependence has developed, the user needs Diazepam to function and prevent the symptoms of withdrawal. Diazepam users often increase their doses to counter withdrawal symptoms as their tolerance to the drug increases.

• Withdrawal from Diazepam can be dangerous, so users should never try to quit “cold turkey.” This can lead to coma and other potentially fatal outcomes. Quitting Diazepam requires medical management as the body and brain recalibrate to be able to function properly without the drug.

• According to the Diagnostic and Statistical Manual of Mental Disorders, it takes as little as 15 mg of Diazepam each day for several months to start experiencing withdrawal symptoms. People who have taken more than 100 mg of Diazepam a day are more likely to experience serious withdrawal symptoms and complications.

• he severity of withdrawal symptoms depends on the period of time the substance was used and how much the user took on a daily basis. Heavy Diazepam use over a long period of time leads to more difficult withdrawal symptoms.

Symptoms of Withdrawal

Abdominal cramps Headache Tremors

Sweating Muscle pain Vomiting

Severe anxiety Confusion Restlessness and insomnia

Numbness Hallucinations Seizures

Diazepam Detox

• Diazepam detox is the process of getting the drugs out of the user’s body. The goal of Diazepam detox is to remove the drugs from the body while minimizing withdrawal symptoms.

• Detoxing from Diazepam can be dangerous without medical guidance. Most Diazepam users who want to quit follow a detox program that gradually reduces their doses, usually on a weekly or bi-weekly basis. This minimizes the uncomfortable withdrawal symptoms and prevents dangerous complications such as seizures.

• The severity of the addiction is the biggest factor on how long detox takes. Those who are more severely addicted take longer to detox because abruptly reducing their Diazepam doses causes harmful withdrawal symptoms.

Treatment for Diazepam Addiction

• Diazepam is a long-acting benzodiazepine, so it can take time for someone’s body to readjust after they decide to quit. Recovering from an addiction to Diazepam often takes a combined approach of tapering down doses and attending therapy.

• For many, withdrawal symptoms are the hardest part of a Diazepam addiction, but medically assisted treatment can ease these symptoms.

• The symptoms are more intense for those who took larger, more frequent doses. The process of Diazepam detox might last anywhere from a few weeks to several months.

• Abruptly quitting can be dangerous.

Treatment for Diazepam Addiction

• Those heavily addicted to Diazepam or who also suffer from an addiction to another substance often choose to begin recovery in rehab.

• There are many Diazepam treatment centers with a strong record of recovery, each with their own approach to addiction treatment.

Treatment for Diazepam Addiction

• Diazepam addiction can be treated on an inpatient or outpatient basis.

• A person who elects for inpatient treatment will need to check into a diazepam rehab facility and remain there for the duration of his or her treatment.

• A person being treated on an outpatient basis will go to the treatment facility on a daily basis (usually excluding weekends and holidays) to meet with an addiction specialist and obtain medications.

• Inpatient treatment is best for people who need to remove themselves from their environments to overcome their addictions.

• The temptation to continue using drugs may be too strong for users to remain in their current environments.

Treatment for Diazepam Addiction

• Drug availability is restricted at inpatient treatment centers. • Additionally, contact with the outside world is usually limited,

especially at the beginning of diazepam addiction treatment. • This allows the person to focus on recovering from the addiction

and improves his or her chances of success.• However, the person will have to leave his or her life for the

duration of the treatment, which could mean a loss of employment.

Treatment for Diazepam Addiction

• Outpatient treatment allows the person remain in his or her environment while being treated for the addiction.

• People in this situation are able to maintain employment and benefit from the support of their social networks.

• Outpatient treatment is usually cheaper than inpatient treatment. • Unfortunately, if the person is in an environment where diazepam

and other drugs are readily available, he or she may give into temptation and relapse.

BENZODIAZEPINE: SLOW SAND OF ADDICTION IN PAKISTAN

• Not only in Pakistan but around the world benzodiazepines are among the most prescribed and consumed medication groups.

• In Pakistan, there is a dearth of properly trained and qualified psychiatrists. The psychiatrist to population ratio is dismally low.

• Almost 67 % population resides in rural areas to which mental health care is delivered by general physicians.

• Prevalence estimates of common mental disorders is about 30% - ranging from 10-to-25% in urban settings to 30-to-66% in rural settings.

• Tranquilizers have become an accepted component in the lives of a large segment of our population.

• By a conservative estimate around seven to ten million urban dwellers in Pakistan continue to consume these medications regularly.

• Most of these medication are available over-the counter without any medical prescription.

• In the context of Pakistan, this has stemmed from their status as sleeping pills; in an overdose one would expect a person to 'sleep forever'. Favorably there pharmacological lethality index is very high. However this in no way makes them any less dangerous than other drugs of overdose.

• In a study done in Pakistan the proportion of Benzodiazepine usage in deliberate self harm, it was more than the double quoted in the western data i.e. 80%.

• However the predominant method of getting these drugs was their availability over the counter in 44% cases, the fact which can be safely generalized to almost all developing nations.

• In the context of Pakistan Pharmaceutical companies, driven by economic gains, marketing these tablets as absolute recipe for peace of mind. Most Physicians act as 'agents' for sales and promotion; with their share in the cake.

• Health care in the private sector is an industry and is driven by the 'profit motive.' Ipso facto, hospitals are less an instrument for providing relief from suffering than money-making machines. The position of medical profession, by and large, is no more, to put it in kind words, a noble profession; self-serving motives dominate.

• Ultimately it is the patients and their families who have to pay the cost - be it the lavish luncheons in five star hotels or cruise trips to exotic location. This is obviously done in the guise of science, technology and promotion of 'robust' evidence

Possible solutions

• In general, the three rules that apply to benzodiazepine are that • Prescribing should be kept to a minimum • Reviewed regularly • Discontinued as soon as possible

Possible solutions:

• Arrange Public awareness program• Organize regular C.M.E programs involving G.P's• Develop Good practice guidelines for drug prescription• Better Drug regulation and dispensing mechanisms• Need to develop and implement Legislation• Early recognition and referral to mental health services• Need to establish well staffed Rehabilitation centers.

References:

• http://www.benzo.org.uk/ashbzab.htm• www.narconon.org/drug-abuse/effects-of-benzodiazepine.html• http://www.addictionrecov.org/Addictions/index.aspx?AID=38• http://www.webmd.com/mental-health/addiction/benzodiazepine-abuse• http://

journals.plos.org/plosone/article/asset?id=info:doi/10.1371/journal.pone.0001804.XML

• http://drugabuse.com/library/valium-abuse/• https://www.addictioncenter.com/benzodiazepines/valium/• http://www.projectknow.com/research/diazepam/• Benzodiazepine: slow sand of addiction. Naqvi H1, Hussan S, Dossa

F. J Pak Med Assoc. 2009 Jun;59(6):415-7.

THANK YOU!!!

THE END