Hello and welcome to the Animal Care Learning Alliance webinar Methadone and buprenorphine, a comparison of veterinary opioids. The main focus of this webinar is to discuss the comparisons between methadone and buprenorphine. In doing so, we will discuss types of opioids, opioid receptors, controlled drugs regulations, and differences in analgesia.

The role of naturally occurring opioids in controlling pain is not clear. Opioid receptors are present in the multiple parts of the nervous system that are involved in pain transmission and control, including the spinal cord and the brain. The main opioid receptors are new and kappa receptors, though 17 receptors have been discovered in total.

New receptors are present throughout the central nervous system. They have a sensory and motor function, altering the transmission of pain messages. Kappa receptors have a main effect of sedation.

And the more recently investigated delta receptors are not as widely distributed. As you can see from the table, the new receptor is mainly responsible for analgesia. With some sedation and a small amount of euphoria, especially in cats.

The kappa receptor is more responsible for sedation with with less analgesic effect and can produce dysphoria or depression. Therefore, it is the action of the mu receptor which dictates the main analgesic properties of our opioids. Inhibition of neurotransmitter release is considered to be the major mechanism of action responsible for the clinical effect of opioids.

However, their full actions within the body are still unknown. This inhibition of neurotransmitter release occurs at the pre-synaptic neuron. Neurotransmitter release is triggered by depolarization of the nerve terminal, a change to positive inside and negative outside.

The opioid acts on the calcium channel, preventing positive calcium flow into the cell. With no depolarization, there is no fusing of the vesicle and no neurotransmitter release. It is also thought that they have a post-synaptic effect, which is also inhibitory.

Opioids open voltage sensitive potassium channels and thus increase outward movement of positive potassium ions from the neuron. This hyperpolarization means the membrane is negative inside and positive outside, thus inhibiting the passing of an action potential. The effects of each opioid depends on the type of agonist the opioid is, the dose given, and the individual and species pharmacokinetics.

Side effects vary depending on type and route of administration and include respiratory depression, cardiovascular effects, and delayed gastric emptying and prolonged intestinal transit time, though this is more commonly seen in humans. The efficacy of a pharmaceutical relates to the maximum biological effect the drug can achieve after binding to a receptor. Drugs that produce maximal expected effect are termed full agonists.

While drugs that combined with receptors but produce less than the expected maximal effect are partial agonists. Therefore, in theory, there is a plateau where the partial agonists bind to more receptors but do not produce a greater effect. So concentrating on methadone and buprenorphine, methadone is a full agonist at the mu receptor, and buprenorphine is a partial agonist at the mu receptor.

Thinking back to the slide of actions of receptors, the new receptors produce a strong analgesic effect. Therefore, methadone produces a maximal analgesic effect at the receptor, but buprenorphine does not. The affinity of a pharmaceutical relates to how well a drug binds to its receptor.

Methadone has a lower affinity for receptors while buprenorphine has a high affinity for receptors. So buprenorphine will bind to more of the available receptors, but produce a less than maximal analgesic effect. While methadone binds or stays bound to less of these receptors in comparison.

But produces a maximal analgesic effect at each it binds to. We can see that at lower doses, methadone and buprenorphine produce effects that are indistinguishable. However, at high doses due to the high receptor affinity of buprenorphine, the receptors may become saturated, and as it is a partial agonist, any dose increase would not increase the analgesic effect.

With methadone, we can see at high doses, with available receptors, the maximal effect to each will have an increasing analgesic effect. This is called the ceiling effect. It is considered, however, to be more theoretical and unlikely to occur at veterinary clinical doses as the level of side effects seen also increases as dosage increases and so treatment is often stopped.

However, it does demonstrate the suitability of methadone in cases of unknown pain level or where top-up pain relief may be required. As we said earlier, there are other opioid receptors involved in analgesia. Methadone also has an effect at the kappa receptor while buprenorphine does not.

Activation of this receptor has a lower analgesic effect, but when combined with activation of the new receptor increases the overall analgesia of methadone. So how do these differences impact use in practise? The aim of analgesia is to reduce the number of pain signals going to the brain to prevent the development of wind-up.

Once windup occurs, it is known that the response to analgesics is reduced. A multimodal approach to analgesia will provide the best results, and considerations for which opioid to use should include the expected severity of pain, other drugs administered, and the duration of analgesia required. Taking all of this into consideration allows for the choice of the most appropriate analgesic.

This table is a summary of all of the key points, including the routes of administration and duration of action, which is slightly different between methadone and buprenorphine. Both of these opioids are controlled drugs, but their requirements are different. Controlled drugs are listed under the Misuse of Drugs Regulations 2001.

Licenced veterinary medicines fall within the schedules 2 to 5. The RCVS website has a very comprehensive guidance document for controlled drugs that it is advisable to read. Special requirements apply, including the writing of prescriptions, storage, record keeping, and destruction of waste product.

Methadone is classed as a Schedule 2 controlled drug, while buprenorphine is a Schedule 3 controlled drug, but it does have some specific storage requirements compared to other Schedule 3 drugs. It is an offence to supply a Schedule 2 or 3 drug against a fax or email prescription. The original copy hand signed in ink, must be obtained before supply is released.

A written prescription for Schedule 2 and 3 controlled drugs is valid for 28 days. Both methadone and buprenorphine, unlike other Schedule 3 controlled drugs, must be kept in a locked container that conforms to British standards and is attached to the fabric of the building. Clients should not normally have access to the room where the control dogs are stored.

And access should be restricted with a key kept by a responsible individual at all times. It is not acceptable to have a communal key, and the cabinet must be kept locked when not in use. Schedule 2 controlled drugs require the practise to maintain a controlled drugs register.

This register has a strict set of requirements which must be complied with. In comparison, Schedule 3 controlled drugs do not need to be recorded in a controlled drugs register, but invoices must be retained for 5 years. Schedule 2 controlled drugs must only be destroyed in the presence of an authorised person and rendered irretrievable.

An authorised person includes a veterinary surgeon, independent of the practise who has no personal, professional or financial interest in the practise. A member of the VMD or an RCVS inspection team member, or a police controlled drugs liaison officer. For Schedule 3 drugs, controlled drugs, there is no legal requirement to have the disposal of waste product witnessed.

Normal pharmaceutical disposal rules apply. This table is a summary of all different legal requirements for the two types of controlled drugs. Taking all this into consideration, we must remember that analgesic protocols need to be adaptable.

Appropriate pain scarring should be carried out to ensure that analgesia is adequate for the individual patients needed. Hopefully, this webinar will have highlighted the similarities and differences between using the two products in practise. And a suitable choice chart is included.