What is a Low-Threshold Treatment Programme?

Introduction

Low-threshold treatment programmes are harm reduction-based health care centres targeted towards people who use substances.

“Low-threshold” programmes are programmes that make minimal demands on the patient, offering services without attempting to control their intake of drugs, and providing counselling only if requested. Low-threshold programmes may be contrasted with “high-threshold” programmes, which require the user to accept a certain level of control and which demand that the patient accept counselling and cease all drug use as a precondition of support.

Low-threshold treatment programmes are distinct from simple needle exchange programmes, and may include comprehensive healthcare and counselling services. The International Journal of Drug Policy in its volume 24 published an Editorial which endeavoured to define a service known to be “low-threshold”, based on some popular and known criteria. According to that Editorial, low-threshold services for drug users can be defined as those which offer services to drug users; do not impose abstinence from drug use as a condition of service access; and endeavour to reduce other documented barriers to service access. Beyond comprehensive needle exchange services, other examples of low-threshold, community-based programmes include those that support people who use alcohol or drugs to consider positive or health protective changes without a demand for “recovery,” such as those piloted in New York City in the 1990s as “recovery readiness” efforts to bolster HIV prevention.

Background

Injection drug users (IDUs) are at risk of a wide range of health problems arising from non-sterile injecting practices, complications of the drug itself or of the lifestyle associated with drug use and dependence. Furthermore, unrelated health problems, such as diabetes, may be neglected because of drug dependence. Sharing of health information with police, or requirements that patients abstain from all illegal drug use prior to receiving support are further impediments to health seeking, or require patients to lie about drug use in order to receive other lifesaving services. For all these reasons, despite their increased health care needs, IDUs do not have the required access to care or may be reluctant to use conventional services. Consequently, their health may deteriorate to a point at which emergency treatment is required, with considerable costs to both the IDUs and the health system. Accordingly, harm reduction based health care centres, also known as targeted health care outlet or low-threshold health care outlet for IDUs have been established across a range of settings utilising a variety of models. These targeted outlets provide integrated, low-threshold services within a harm-reduction framework targeting IDUs, and sometimes include social and/or other services. Where a particular service is not provided, referral and assistance with access is available. In 2007, for example, 33% of all US needle-syringe programmes (NSPs) provided on-site medical care, and 7% provided buprenorphine treatment. Similarly, in many European countries NSP outlets serve as low-threshold primary health care centres targeting primarily IDUs.

Health Care Models

These targeted outlets vary widely and may be either “distributive”, providing basic harm reduction services and simple healthcare with facilitated referrals to specialist services, or “one-stop-shops” where a range of services including specialist services are provided onsite. The services being offered by these outlets range from simple needle and syringe provision, to expanded services including basic and preventive primary healthcare, hepatitis B and A vaccinations, hepatitis C testing, counselling, tuberculosis screening and sometimes opioid maintenance therapy. Some centres offer hepatitis, HIV treatment and dental care. The goal of these outlets is to provide:

  • Opportunistic health care;
  • Increased temporal and spatial availability of health care;
  • Trustworthy services of health care;
  • Cost-effective mode of health care; and
  • Targeted and tailored services.

In the United States as of 2011, 211 NSPs were known to be operating in 32 states, the District of Columbia, Puerto Rico and the Indian Nations. The bulk of funding has come from state and local governments, since for most of the last several decades, federal funding for needle exchange programs has been specifically banned.

Globally, as of 2008, at least 77 countries and territories offer NSPs with varying structures, aims, and goals. Some countries use needle exchange services as part of integrated programmes to contain drug use, while others aim simply to contain HIV infection as their top priority, considering a reduction in the incidence of drug use as a much lower priority. Acceptance of NSPs vary widely from country to country. On the one hand, in Australia and New Zealand, electronic dispensing machines are available at selected locations such as the Auckland needle exchange and the Christchurch needle exchange, allowing needle exchange service 24 hours to registered users. On the other hand, over half of the countries in Asia, the Middle East, and North Africa retain the death penalty for drug offenses, although some have not carried out executions in recent years.

Evaluation

Low-threshold programmes offering needle exchange have faced much opposition on political and moral grounds. Concerns are often expressed that NSPs may encourage drug use, or may actually increase the number of dirty needles in the community. Another fear is that NSPs may draw drug activity into the communities in which they operate. It has also been argued that in fighting disease, needle exchanges take attention away from bigger drug problems, and that, contrary to saving lives, they actually contribute to drug-related deaths. Even in Australia, which is considered a leading country in harm reduction, a survey showed that a third of the public believed that NSPs encouraged drug use, and 20% believed that NSPs dispensed drugs. In the United States, the ambivalent public attitude towards NSPs is often reflected in police interference, with 43% of NSP programme managers reporting frequent (at least monthly) client harassment, 31% reporting frequent confiscation of clients’ syringes, 12% reporting frequent client arrest, and 26% reporting uninvited police appearances at programme sites. A single 1997 study which showed a correlation between frequent programme use and elevated rates of HIV infection among IDUs in Vancouver, Canada, has become widely cited by opponents of NSPs as demonstrating their counter-productiveness.

Authors from the 1997 Vancouver study have, in multiple publications, issued disclaimers against the misuse of their work by opponents of NSPs. They point out that frequent attendees of the program tended to be young and often indulged in extreme high-risk behaviours. The 1997 results were hence of statistically biased sampling. They have emphasized that the correct message to be derived from their 1997 study can be read in the title of their work: “Needle exchange is not enough”. This is the same message presented by many other articles since.

Comprehensive, systematic surveys of the costs and effectiveness of low-threshold primary healthcare programmes are not available due to the heterogeneity of these programmes and the study designs. Narrower focus studies dealing solely with the needle exchange issue are abundant, however, and generally support the thesis that NSPs reduce the risk of prevalence of HIV, hepatitis and other blood-borne diseases. These studies suggest that such outlets improve the overall health status of IDUs and save on the health budget by reducing episodes in emergency departments and tertiary hospitals. In Australia, monitoring of drug users participating in NSPs showed the incidence of HIV among NSP clients to be essentially identical to that of the general population. Fears that NSPs may draw drug activity into the communities in which they operate are contradicted by a study that showed that by far the greatest number of clients of an NSP in Chicago came to the area to exchange needles (60%) rather than to buy drugs (3.8%).

Internationally, support for the effectiveness of low-threshold programmes including needle exchange have come from studies conducted in Afghanistan, China, Spain, Taiwan, Estonia, Canada, Iran, and many other countries. However, in many countries, there is strong opposition to such programmes.

Despite the lack of randomised clinical trials demonstrating the impact of low-threshold services, the available evidence, barriers to service access and the late presentation of seriously ill IDUs to hospital, suggests the ongoing need for targeted and low-threshold services. In addition, prevention of HIV and hepatitis C transmission is clearly possible for those unable or unwilling to stop injecting drug use, and a range of countries using low-threshold approach have achieved control or virtual elimination of HIV transmission among people who inject drugs. For these reasons, organisations ranging from the US National Institutes of Health, the Centres for Disease Control, the American Bar Association, the American Medical Association, the American Psychological Association, the World Health Organisation, the European Monitoring Centre for Drugs and Drug Addiction and many others have endorsed low-threshold programmes including needle exchange.

What is Flutoprazepam?

Introduction

Flutoprazepam (Restas) is a drug which is a benzodiazepine.

It was patented in Japan by Sumitomo in 1972 and its medical use remains mostly confined to that country. Its muscle relaxant properties are approximately equivalent to those of diazepam – however, it has more powerful sedative, hypnotic, anxiolytic and anticonvulsant effects and is around four times more potent by weight compared to diazepam. It is longer acting than diazepam due to its long-acting active metabolites, which contribute significantly to its effects. Its principal active metabolite is n-desalkylflurazepam, also known as norflurazepam, which is also a principal metabolite of flurazepam (trade name Dalmane).

Flutoprazepam is typically used for the treatment of severe insomnia and may also be used for treating stomach ulcers.

Flutoprazepam does not fall under the international Convention on Psychotropic Substances of 1971, and is currently unscheduled in the United States.

  • In Singapore, flutoprazepam is a Class C-Schedule II drug under the Misuse of Drugs Act.
  • In Thailand, flutoprazepam is a Schedule III psychotropic substance.
  • In Hong Kong, flutoprazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance.
    • Flutoprazepam can only be used legally 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 $10000 (HKD).
    • The 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.

What is Flunitrazolam?

Introduction

Flunitrazolam (FNTZ, Flunazolam) is a triazolobenzodiazepine (TBZD), which are benzodiazepine (BZD) derivatives, that has been sold online as a designer drug, and is a potent hypnotic and sedative drug similar to related compounds such as flunitrazepam, clonazolam and flubromazolam.

Background

It was first definitively identified and reported to the EMCDDA Early Warning System, by an analytical laboratory in Germany in October 2016, and had not been described in the scientific or patent literature before this.

It is the triazole analogue of Flunitrazepam (Rohypnol).

The addition of the triazole ring to the scaffold increases potency significantly, this is evident as flunitrazolam is reported anecdotally to be active in the microgram level.

What is Flubromazepam?

Introduction

Flubromazepam is a benzodiazepine derivative which was first synthesized in 1960, but was never marketed and did not receive any further attention or study until late 2012 when it appeared on the grey market as a novel designer drug.

It is a structural analogue of phenazepam in which the chlorine atom has been replaced by a fluorine atom.

An alternative isomer, 5-(2-bromophenyl)-7-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one or “iso-flubromazepam”, may have been sold under the same name.

United Kingdom

In the UK, flubromazepam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

United States

Flubromazepam, clonazolam, and flubromazolam are Schedule I controlled substances under Virginia State Law.

What is Delorazepam?

Introduction

Delorazepam, also known as chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam.

It is marketed in Italy, where it is available under the trade name EN and Dadumir. Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. Adverse effects may include hangover type effects, drowsiness, behavioural impairments and short-term memory impairments. Similar to other benzodiazepines delorazepam has anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties.

Indications

Delorazepam is mainly used as an anxiolytic because of its long elimination half-life; showing superiority over the short-acting drug lorazepam. In comparison with the antidepressant drugs, paroxetine and imipramine, delorazepam was found to be more effective in the short-term but after 4 weeks the antidepressants showed superior anti-anxiety effects.

Delorazepam is also used as a premedication for dental phobia for its anxiolytic properties. High doses of Delorazepam may be administered the night before a dental (or other medical) procedure in order to provide relief from anxiety-associated insomnia that night with the effects persisting long enough to sufficiently treat anxiety the next day.

Delorazepam has also demonstrated effectiveness in treating alcohol withdrawal.

Availability

Delorazepam is available in tablet and liquid drop formulations. The liquid drop formulation is absorbed more quickly and has improved bioavailibility.

Pharmacology

Delorazepam is well absorbed after administration, reaching peak plasma levels within 1-2 hours. It has a very long elimination half-life and can still be detected 72 hours after dosing. Bioavailability is about 77%. Peak plasma levels occur at just over one hour after administration. Significant accumulation occurs of delorazepam due to its slow metabolism; the elderly metabolise delorazepam and its active metabolite slower than younger individuals, resulting in a dose of delorazepam accumulating faster and peaking at a higher plasma concentration than an equal dose administered to a younger individual. The elderly also have a poorer response to the therapeutic effects and a higher rate of adverse effects. The elimination half-life of delorazepam is 80-115 hours. The active metabolite of delorazepam is lorazepam and represents about 15-24% of the parent drug (delorazepam). The pharmacokinetics of delorazepam are not altered if it is taken with food, except for some slowing of absorption. Delorazepams potency is approximately equal to that of lorazepam, being ten times more potent by weight than diazepam (1 mg delorazepam = 1 mg lorazepam = 5 mg diazepam), typical doses range from 0.5 mg-2 mg. Treatment is generally initiated at 1 mg for healthy adults and 0.5 mg in paediatric and geriatric patients and patients with mild renal impairment, treatment is contraindicated in patients with moderate or severe renal impairment.

Side Effects and Contraindications

Delorazepam hosts all the classic side-effects of GABAA full agonists (such as most benzodiazepines). These include sedation/somnolence, dizziness/ataxia, amnesia, reduced inhibition, increased talkativeness/sociability, euphoria, impaired judgement, hallucinations, and respiratory depression. Paradoxical reactions including increased anxiety, excitation, and aggression may occur and are more common in elderly, paediatric, and schizophrenic patients. In rare instances, delorazepam may cause suicidal ideation and actions.

Long term use of delorazepam (as well as all other benzodiazepines) has been found to increase long term cognitive deficits (persisting longer than sixth months) which some researchers claim to be permanent. Short term use may occasionally cause depression and the risk of depressive symptoms occurring increases considerably with longer terms of use, delorazepam is not intended to be used for more than 2-4 weeks unless it used only occasionally on an as-needed basis. When being used on an as-needed basis the need for delorazepam therapy should be re-evaluated each time a new prescription for delorazepam is issued, and alternative medications should be considered if patients begin to take delorazepam habitually (many days in a row).

The most serious effect of long term delorazepam use is dependence, with withdrawal symptoms which mimic delirium tremens presenting when delorazepam use is discontinued. Although the withdrawal effects from delorazepam are generally less severe than its shorter-acting counterparts, they can be life-threatening. Slow de-titration of delorazepam over a period of weeks or months is generally suggested to minimise the severity of withdrawal. Psychological effects of withdrawal such as rebound anxiety and insomnia have been known to persist for months after physical dependence has been successfully treated.

Delorazepam is contraindicated in those with severe schizophrenia or schizo-affective disorders, those with a known allergy or hypersensitivity to delorazepam or related benzodiazepines, and those with moderate to severe renal impairment (delorazepam is sometimes administered at a reduced dose to patients with mild renal impairment). Delorazepam is generally considered to be contraindicated in patients with severe acute or chronic illnesses but is occasionally used in the palliative care of terminal patients during their last days/weeks of life.

Patients with a history of substance and/or alcohol use are believed to have an increased risk of abusing delorazepam (as well as all other benzodiazepines), this must be considered when a physician prescribes delorazepam to such patients. Although all patients being treated with delorazepam should be routinely monitored for signs of use and diversion of medication, increased monitoring of patients with a history of substance and/or alcohol use is always warranted. Non-medical benzodiazepine use in patients who have them prescribed on an as-needed basis for chronic/refractory anxiety, insomnia, and intermittent muscle spasms has occurred and generally occurs very slowly, becoming evident only after months or years since the initiation of therapy. Monitoring of patients actively using delorazepam should never be discontinued even if the patients has been stable on the medication for many months or years.

Caution must be used when delorazepam is administered alongside other sedative medications (ex. opiates, barbiturates, z-drugs, and phenothiazines) due to an increased risk of sedation, ataxia, and (potentially fatal) respiratory depression. Although overdoses of benzodiazepines alone rarely result in death, the combination of benzodiazepines and other sedatives (particularly other gabaminergic drugs such as barbiturates and alcohol) is far more likely to result in death.

Special Cautions

People with renal failure on haemodialysis have a slow elimination rate and a reduced volume of distribution of the drug. Liver disease has a profound effect on the elimination rate of delorazepam, resulting in the half-life almost doubling to 395 hours, whereas healthy patients showed an elimination half-life of 204 hours on average. Caution is recommended when using delorazepam in patients with liver disease.

What is Antipsychotic Switching?

Introduction

Antipsychotic switching refers to the process of switching out one antipsychotic for another antipsychotic.

There are multiple indications for switching antipsychotics, including inadequate efficacy and drug intolerance. There are several strategies that have been theorised for antipsychotic switching, based upon the timing of discontinuation and tapering of the original antipsychotic and the timing of initiation and titration of the new antipsychotic. Major adverse effects from antipsychotic switching may include supersensitivity syndromes, withdrawal, and rebound syndromes.

Rationale

Antipsychotics may be switched due to inadequate efficacy, drug intolerance, patient/guardian preference, drug regimen simplification, or for economic reasons.

RationaleOutline
Inadequate Efficacy1. An inadequate treatment response to an antipsychotic, assuming that the lack of efficacy is due to an otherwise adequately dosed regimen for an appropriate duration, can result from failure to achieve therapeutic goals in any major treatment domain.
2. For example, this can refer to a patient who becomes acutely psychotic after being stable previously.
3. Other failures include persistent symptoms of schizophrenia, either positive or negative, problems with mood (including suicidality), or problems with cognition. Inadequate efficacy may be due to nonadherence to therapy, which can influence treatment decisions.
4. For example, long acting injectable (LAI) antipsychotics are often indicated in the setting of medication nonadherence.
Drug Intolerance1. Adverse effects can contribute to drug intolerance, potentially necessitating antipsychotic switching.
2. Adverse effects that threaten serious harm, aggravate other medical conditions, or make a person want to stop taking their medications are all examples of drug intolerance.
3. Certain drug interactions can cause adverse effects as well.
Patient/Guardian Preference1. A patient or caregiver may prefer a different antipsychotic.
2. This may be due to misinformation regarding the antipsychotic, including its side effects, a lack of insight into the importance of the medication and the severity of the disease, or overestimating the therapeutic effect.
Drug Regimen Simplification1. Adherence to medication therapy is inversely related to the frequency of dosing.
2. The antipsychotic quetiapine is typically dosed two to three times daily for the management of schizophrenia.
3. A simpler regimen would be a once daily administered antipsychotic.
4. For example, risperidone can be administered once daily.
5. A lack of adherence can lead to poor health outcomes, as well as unnecessary financial burden.
Economics1. A patient or caregiver may request antipsychotic switching to reduce medication costs.
2. The following is an estimate of the direct costs of living with schizophrenia per patient across select countries (annual direct costs in US$):
a. Belgium: 12,050.
b. People’s Republic of China: 700.
c. South Korea: 2,600.
d. Taiwan: 2,115.
e. UK: 3,420.
f. US: 15,464.

Contraindications

In general, contraindications to antipsychotic switching are cases in which the risk of switching outweighs the potential benefit. Contraindications to antipsychotic switching include effective treatment of an acute psychotic episode, patients stable on a LAI antipsychotic with a history of poor adherence, and stable patients with a history of self-injurious behaviour, violent behaviour, or significant self-neglect or other symptoms.

Strategies

There are multiple strategies available for switching antipsychotics. An abrupt switch involves abruptly switching from one antipsychotic to the other without any titration. A cross-taper is accomplished by gradually discontinuing the pre-switch antipsychotic while simultaneously up-titrating the new antipsychotic. An overlap and discontinuation switch involves maintaining the pre-switch antipsychotic until the new antipsychotic is gradually titrated up, then gradually titrating down on the pre-switch antipsychotic. Alternatively, in an ascending taper switch, the pre-switch antipsychotic can be abruptly discontinued. Another alternative, known as the descending taper switch, involves slowly discontinuing the pre-switch antipsychotic while abruptly starting the new antipsychotic. These switching strategies can be further subdivided by the inclusion or exclusion of a plateau period.

See the figure below for a graphic visualisation of the five main antipsychotic switching strategies discussed above.

Antipsychotic Switching Diagram.

Due to differences in how individual antipsychotics work, even within each generation, the process of switching between antipsychotics has become more complex.

Adverse Effects

The three major adverse effects of antipsychotic switching are supersensitivity syndromes, withdrawal, and rebound syndromes.

Supersensitivity Syndromes

Antipsychotics work by antagonising the dopamine receptor D2 (D2R) in the mesolimbic pathway of the brain. When the D2R is suppressed, the neurons may become sensitised to the effect of an endogenous ligand (i.e. dopamine) by up-regulating the production of postsynaptic D2Rs. If the D2 receptors are not subsequently suppressed at previous levels after an abrupt discontinuation of an antipsychotic (e.g. after switching to weak D2R antagonists quetiapine or clozapine), a rebound/supersensitivity psychosis may occur due to the overwhelming effect of endogenous dopamine on sensitised neurons. Supersensitivity psychosis, also called rapid-onset psychosis, must be distinguished from a relapse or exacerbation of the underlying disease (e.g. schizophrenia). Dopamine supersensitivity psychosis generally occurs around 6 weeks after an oral antipsychotic is discontinued, or 3 months after a LAI antipsychotic is discontinued. In addition, supersensitivity psychosis is generally easier to reverse by reintroducing D2R antagonism (i.e. restarting the discontinued drug), whereas a relapsed schizophrenia is more difficult to control.

Rebound Syndromes

The second-generation antipsychotic olanzapine is thought to have a rebound-induced hyperthermia, which may be mediated by serotonin receptors. Hyperthermia, or elevated core body temperature, is associated with neuroleptic malignant syndrome, a potentially lethal syndrome that commonly occurs due to excessive D2R antagonism (As a point of contrast, hypothermia, or low core body temperature, has most frequently occurred in the presence of olanzapine, risperidone, or haloperidol).

In general, rebound D2R activity may induce rebound parkinsonism and rebound akathisia.

Withdrawal

D2 receptor activity withdrawal may induce withdrawal dyskinesia. This late-onset, hypersensitivity-type dyskinesia is in contrast to the early-onset dyskinesia that can occur due to an over-compensatory dopamine release associated with abrupt dopamine antagonist withdrawal. Other symptoms of dopamine withdrawal include difficulty sleeping, anxiety, and restlessness.

Alternatives

An alternative to antipsychotic switching, in the setting of a person that is not responding to the initial dose of an antipsychotic, is to increase the dose of antipsychotic prescribed. A 2018 Cochrane review compared the evidence between the two strategies, but the authors were unable to draw any conclusions about whether either method was preferable due to limited evidence.

What is an Atypical Antidepressant?

Introduction

An atypical antidepressant is any antidepressant medication that acts in a manner that is different from that of most other antidepressants.

Refer to Second-Generation Antidepressant, Tricyclic Antidepressant, and Tetracyclic Antidepressant.

Background

Atypical antidepressants include agomelatine, bupropion, mianserin, mirtazapine, nefazodone, opipramol, tianeptine, and trazodone. The agents vilazodone and vortioxetine are partly atypical. Typical antidepressants include the SSRIs, SNRIs, TCAs, and MAOIs, which act mainly by increasing the levels of the monoamine neurotransmitters serotonin and/or norepinephrine. Among TCAs, trimipramine is an atypical agent in that it appears not to do this. In August 2020, Esketamine (JNJ-54135419) was approved by the US Food and Drug Administration (FDA) for the treatment for treatment-resistant depression with the added indication for the short-term treatment of suicidal thoughts.

Buprenorphine/Samidorphan (ALKS-5461) is an antidepressant with a novel mechanism of action which is under development and is considered an atypical antidepressant. They act faster than available antidepressants.