Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, November 2016
Scheduling medicines and poisons
Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)
2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS-ACMS #14)
Referred scheduling proposal
The delegate is considering up-scheduling pentobarbital (pentobarbitone) when packed and labelled for injection from Schedule 4 (Prescription Only Medicine or Prescription Animal Remedy) to Schedule 8 (Controlled Drug). This is due to the reported misuse of injectable pentobarbital and its involvement in suicides and whether the greater access control of Schedule 8 is more appropriate.
Current scheduling status and relevant scheduling history
Pentobarbital is currently listed in Schedule 4, Schedule 8 and Appendix K, as follows:
PENTOBARBITAL except when included in Schedule 4.
PENTOBARBITAL when packed and labelled for injection.
cross reference: PENTOBARBITAL
Other barbiturates are currently listed in the Poisons Standard as follows:
- Schedule 8 (butobarbitone, cyclobarbitone, secbutobarbitone and quinalbarbitone) with Appendix K entries;
- Schedule 4 when packed and labelled for injection and Schedule 8 for other uses (amylobarbital);
- Schedule 4 (methylphenobarbital, phenobarbital, and barbiturates except when separately specified).
Relevant scheduling history
In January 1955, at the first meeting of the Poisons Schedule committee, barbituric acid was placed in Schedule 4, with concentrations of barbituric acid below 1% placed in Schedule 2.
In July 1968, the Poisons Schedule Sub-Committee (PSC) suggested that barbiturate tablets should be strip packed, following an article in the Medical Journal of Australia raising concern that some attempts at suicide could be avoided if barbiturate drugs were individually wrapped in tin foil, rather than packed in bottles.
In June 1980, the committee considered barbiturate scheduling, following media reports of proposed changes in NSW relating to availability and the Capital Territory Health Commission Deputy Chair's concerns around danger and abuse of barbiturates. The committee sought views of the Pharmaceutical Benefits Advisory committee (PBAC), the Department of Veterans' Affairs (DVA), Australian Drug Evaluation committee (ADEC) and the Medicines Advisory committee on the use of barbiturates in medical practice.
In November 1980, the committee considered a minute from the Secretary of the Dental Health committee listing pentobarbitone and other barbiturates as necessary for anaesthesia and conscious sedation in dental practice. Other views of the MAC were presented and included use in the treatment of cholestasis of pregnancy, management of jaundice and infantile colic. A direction from the Public Health Advisory committee (October 1980) meeting to PSC required examination of barbiturate use and advice on appropriate methods of control. It was agreed that ramifications of placing barbiturates in Schedule 8 would be considered at the next meeting.
In March 1981, the November 1980 meeting’s proposal to retain barbiturate group of drugs in Schedule 4 for use to treat epilepsy and for anaesthesia and reclassify all other as Schedule 8 was considered. A consensus was not reached and the matter referred to the May 1981 meeting. Members were to raise the matter with their own Poisons Advisory committees.
In May 1981, the committee received correspondence from the WA Commissioner for Public Health indicating that the WA Poisons Advisory committee favoured tightening supplies of barbiturates rather than reclassification into Schedule 8. There was general agreement that barbiturates should be included in Appendix D. A final decision on barbiturates was deferred to the next meeting.
In August 1985, the committee was advised that Queensland intended to allocate many barbiturates to Schedule 8, with other states initiating legislation for Schedule 8 as well. In August 1985, the committee recommended that barbiturates be included in Schedule 8, with the original Schedule 4 remaining for parenterals [i.e. delivery by injection] during a phasing-in period [i.e. implementation date] of 6-12 months.
Schedule 4 - PENTOBARBITONE when packed and labelled for injection
Schedule 8 - PENTOBARBITONE except when included in Schedule 4
In November 1986, the committee noted ADEC's view that barbiturates were used as anticonvulsants and parenteral barbiturate formulations should be excluded from any Schedule 8 proposals. Members were informed of the Ministerial Council on Drug Strategy adopting the scheduling proposal (excluding barbiturate anticonvulsants from Schedule 8).
In February 1987, the TAS member reported changing the wording of the barbiturate entries so that they are similar to the Poisons Standard. WA reported that barbiturates have been S8 for some months now and barbiturate prescriptions were reported.
This was a delegate-initiated application. The delegate's proposed amendments to the Poisons Standard are as follows:
Schedule 8 - Amend entry
except when included in Schedule 4.
Schedule 4 - Delete entry
PENTOBARBITAL when packed and labelled for injection.
The delegate-initiated rescheduling proposal is due to the reported misuse of injectable pentobarbital and its involvement in suicides and whether the greater access control of Schedule 8 is more appropriate.
USA: In the United States of America, pentobarbital (as a derivative of barbituric acid) is a Schedule III Controlled Substance, along with narcotics such as amphetamine and other substances such as nalorphine, glutethimide and anabolic steroids (https://www.law.cornell.edu/uscode/text/21/812), from 27 October 1970. Anabolic steroids and other chemicals including barbital and phenobarbital were added to Schedule III in 1990.
UN: While it is a Class III psychotropic substance of the United Nations Convention on Psychotropic Substances 1971, no country that is a signatory to the convention has prohibited its import (as of the 2016 edition of the Green List of the International Narcotics Control Board).
UK: It is a Class B Controlled Drug in the United Kingdom, from 1 January 1985. It is a Schedule IV Controlled Drug under the Controlled Drugs and Substances Act in Canada.
Barbiturates are substituted pyrimidine derivatives in which the common structure, barbituric acid, has no CNS activity. CNS activity is conferred by substituting alkyl, alkenyl or aryl groups on the pyrimidine ring. Barbiturates are primarily used as sedative hypnotics and also anticonvulsants in sub-hypnotic doses.
Short-acting barbiturates are well absorbed (primarily from the small intestine), with the onset of action being more rapid than with long- or intermediate-acting barbiturates.
The relative lipophilicity of each barbiturate determines the extent that they partition into fat. At steady state, the highest concentration of barbiturate in non-adipose tissue occurs in the liver and the kidney. The bio-transformation of most short-acting barbiturates occurs in the liver, where side-chains are oxidised to more polar and inactive compounds (e.g. alcohols, ketones, phenols or carboxylic acid) (Ellenhorn, 1988).
Pentobarbital (Figure 2.2A) is a short-acting barbiturate that is effective as an anaesthetic and euthanasia treatment for animals due to the nonselective central nervous system (CNS) depressant action. The sodium salt (Figure 2.2B) occurs as a white, slightly bitter powder which is freely soluble in water and alcohol but practically insoluble in benzene and ether (FDA, 2012).
Figure 2.2: Structure of pentobarbital (A) and pentobarbital sodium (B)
|IUPAC name||5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione||5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione sodium salt|
|Human therapeutic names||Carbrital; Nembutal; Pentalgin (with codeine and paracetamol); and Pentobarbitone|
|Veterinary names||Valabarb Euthanasia Solution; Lethabarb Euthanasia Injection; Lethapharm Euthanasia Injection; Illium Pentobarbitone Sodium Anaesthetic Injection; and Euthanimal 40% Euthanasia Injection.|
|Other names||Pentobarbitone; 5-ethyl-5-(1-methylbutyl) barbituric acid; 5-ethyl-5-(sec-pentyl)barbituric acid; pentobarbituric acid; ethaminal; mebubarbital; NSC 28708; nembutal; neodorm||Sodium 5-ethyl-5-(1-methylbutyl) barbiturate; sodium 5-ethyl-4,6-dioxo-5-(pentan-2-yl)-1,4,5,6-tetrahydropyrimidin-2-olate; auropan; barpental; biosedan; butylone; diabutal; embutal; entobar; etaminal sodium; ethaminal sodium; euthanyl; euthatal; isobar; mebubarbital sodium; mebumal sodium; mebunat; NSC 10816; napental; narcoren; nembutal sodium; pacifan; pental; pentobarbital sodium; pentobarbitone sodium; pentonal; pentone; praecicalm; RS-pentobarbital sodium; sagatal; sodium 5-ethyl-5-(1-methylbutyl)barbiturate; sodium ethaminal; sodium Nembutal; sodium pental; sodium pentobarbital; sodium pentobarbitone; sodium pentobarbiturate; sodium-pent; soluble pentobarbital; somnopentyl; somnotol; sopental; sotyl; V-pento; vetbutal|
|Molecular Weight||226.27 g/mol||249.26 g/mol|
Pre-meeting public submissions
Of the 32 pre-meeting submissions received, 7 supported and 25 opposed the proposal.
The main points supporting the proposal were as follows:
- Support for all procedures that assist with the duty of care to staff.
- Agree pentobarbital should have stricter regulations for storage, particularly when the premises are unattended.
- Ease of current access is of concern.
- Some veterinarians already meet Schedule 8 requirements, or exceed Schedule 4 requirements for storage of pentobarbital.
- Veterinarians already maintain a register and have a safe for other Schedule 8 drugs, so this would not be a new process.
- Risk warrants additional licensing.
- Preference for locked cupboard or safe, without other Schedule 8 requirements.
The main points opposing the proposal were as follows:
- Pentobarbital is required for humane euthanasia of animals. Without easy access, there is the potential for animal welfare to be compromised.
- Concern there will be a compromise in animal welfare without reducing the number of suicides by veterinarians.
- Education around mental health is a more appropriate means of reducing suicide rates in veterinarians.
- Other lethal drugs are available as Schedule 4 poisons.
- Illicit trade in pentobarbital will still exist.
- Data provided shows low rate of suicides in Queensland between 2008-2010 attributable to barbiturates (0.3% in 2008-2010).
- Many reported deaths from pentobarbitone were from unknown sources or imported products.
- Current information on suicide using pentobarbital is limited and recommends a more detailed examination of the reported suicides to gain a better understanding of the issue.
- Moving to Schedule 8 will be onerous on veterinarians, both in requiring a larger Schedule 8 safe (cost involved) and in maintaining a register (more red tape).
- As euthanasia is traumatic for the vet, nurse and family, any register may not be accurate.
- Emotional burden currently shared with other authorised staff would be shifted to veterinarians.
- The size of the bottle (500 mL) is of concern. While this is practical for veterinary needs, it is not practical for storage and does not fit in existing Schedule 8 safes.
- Audit requirements won't necessarily catch diversion.
- The variable dose requirements for animal euthanasia would make skimming possible regardless of regulation.
- Increasing the Schedule 8 volumes controlled by the jurisdictions to accommodate the large quantities of pentobarbital would potentially loosen the control over other Schedule 8 drugs.
- Creates uncertainty in relation to transport and storage of pentobarbital in vehicles.
- Community groups would no longer have access, resulting in an increased diversion of injured animals to veterinary professionals to euthanase.
- Support for better storage however questions the need for Schedule 8.
- Pentobarbital be included in Schedule 4, Appendix D, mandating storage and record keeping rather than in Schedule 8.
- Schedule 4, Appendix D classification for pentobarbital already exists in some jurisdictions (e.g. NSW) or practices reflect it.
- Storage requirements that exceed those for Schedule 4 and are similar to Schedule 8 are already practiced in some organisations.
- Concern that meeting any veterinarian's Schedule 8 compliance requirements would involve the veterinary nurses. This is foreseen to place veterinary nurses in a difficult position.
- Pentobarbitone does not meet the factors for Controlled Drugs (Schedule 8) in the AHMAC Scheduling Policy for Medicines and Chemicals (1 February 2015).
- Requests a longer implementation date of at least 12 months if up scheduling occurs.
- Changes to packaging size and additional labelling in conjunction with access controls as an alternative to Schedule 8.
- Staff safety would be compromised in locations that required the transportation of sick and injured animals to external sites with veterinarians for euthanasia.
- Provision of exemptions requested if up scheduled to Schedule 8. To enable professional representative bodies and organisations to endorse non-veterinarians to be accredited in the access and use of pentobarbitone.
Summary of Joint ACCS-ACMS advice to the delegates
The committee advised that the current scheduling of pentobarbital remains appropriate.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) the risks and benefits of the use of a substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of a substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the advice comprised the following:
- Pentobarbital is not registered for use in humans. Narrow therapeutic window. Significant risk of Central nervous system (CNS)/respiratory depression.
- Benefits include cheap and efficient medicine for the humane euthanasia of animals in multiple settings. High mortality when used for self-harm purposes.
- Principal use is as an animal euthanasia product, for which it is the preferred agent and is widely used. The intended effect is death for animals that are suffering or have the potential to do so by central nervous system (CNS) and respiratory depression.
- Pentobarbital IV in 500 mL bottle is more widely used. This seems to be a major impediment to Schedule 8 because it does not fit into existing safes.
- There is potential for misuse for suicidal purposes. The lethal dose for humans is approximately 2-10 g.
- A wide range of authoritative organisations opposed the rescheduling on the basis of reasonable and practical grounds. Impact on suicide is unclear, but potentially low when considered in the entirety of suicides.
The delegates considered the following in regards to this proposal:
- Scheduling proposal
- Joint ACCS-ACMS advice
- Public submissions received
- Section 52E of the Therapeutic Goods Act 1989
- Scheduling Policy Framework (SPF 2015)
- Other relevant information.
Delegates' interim decision
The delegates' interim decision is that the current scheduling of pentobarbital remains appropriate.
The delegates also recommend that the state and territory governments consider standardisation of the controls under their legislation.
The delegates considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: a) the risks and benefits of the use of a substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of a substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.
The reasons for the interim decision are the following:
- The delegates acknowledge and agree with the committee's advice.
- Pentobarbital is not registered for use in humans. It has a narrow therapeutic window and a significant risk of central nervous system (CNS)/respiratory depression. There is potential for misuse for suicidal purposes. The lethal dose for humans is approximately 2 10 grams.
- Pentobarbital is a cheap and efficient medicine, and is the preferred agent and is widely used for the humane euthanasia of animals in multiple settings. The intended effect is death by CNS and respiratory depression for animals that are suffering.
- Pentobarbital in 500 mL bottles is widely used due to the large doses required (predominately in the field) to humanely euthanize large animals or multiple livestock. From a practical perspective, the delegates note that veterinarian access to parenteral solution of pentobarbital in 500 mL bottles for field use is required and is consistent with the current Schedule 4 entry.
- A wide range of authoritative organisations opposed the up-scheduling on the basis of reasonable and practical grounds. Impact on intentional suicide is unclear, but was thought to be low when considering the available data of suicides, and the people that were misusing pentobarbital for suicidal purposes.