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Holistic Cough & Cold management:

pharmacology overview

Dr. Machel Leuschner

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DISCLAIMER

The views and opinions expressed in and during this presentation are those of the author and do not necessarily reflect the official policy or position of the South African Health Products Regulatory Authority (SAHPRA) or the Codeine Care Initiative (CCI). Any content provided by the presenter are of their opinion and are not intended to malign any religion, ethnic group, club, organization, company, individual or anyone or anything.

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Codeine conundrum

Opioid – narcotic
Anti-tussive
Euphoriant effects
Careful monitoring and control is imperative

Known potential for dependence
Mixed with Sprite or alcohol to make a drink called “lean”

A study of 31 countries found that South Africa made up a third of all over-the-counter codeine sales between 2013 and 2019

Misuse and abuse

Following the recent investigation into the illicit bulk sales of codeine-based cough mixtures in violation of the Medicines Control Act, there is a renewed focus on the responsible use of these medicines. The abuse of codeine is unfortunately becoming a ubiquitous practice and a study of 31 countries found that South Africa made up a third of all over-the-counter codeine sales between 2013 and 2019. It is sometimes mixed with Sprite or alcohol to make a drink called “lean”. Codeine is classified as an opioid or narcotic with a known potential for dependence. Clinically, codeine is used to suppress non-productive coughs. However, it can induce a range of warm, fuzzy, and euphoric effects which can lead to misuse and dependence, making it a substance that requires careful monitoring and control.

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PIT and Patient Practices

Pharmacist Initiated Therapy (PIT)
Accessibility of codeine containing products
Lack of a national sector-wide database
No patient history of dispensed codeine containing products
Importance of Codeine Care Initiative

Pharmacy hopping is a concern; Unmonitored access can lead to overuse, overdosing and may also result in addiction and subsequent abuse

Cold and flu medication + cough syrup + pain medication OTC could unknowingly triple recommended dosage

Access Control

Accidental overdose

https://www.samrc.ac.za/reports/SADHS2016 - South Africa Demographic and Health Survey 2016; https://www.ncbi.nlm.nih.gov/pubmed/24091483

Currently, several countries supply codeine-containing medicines as Pharmacist Initiated Therapy (PIT) including the United States of America, United Kingdom, Canada, Germany and South Africa. Although there are limited statistics available, it is common knowledge that these products are at times overused and misused by certain patients who acquire the medicine through deception and/or pharmacy-hopping. However, overuse and misuse often occur through no intentional fault of the patient or pharmacist due to the lack of access to a full patient medication history. Accidental overdosing can happen where a patient may require a cold and flu preparation, plus a cough syrup and then add pain medication without realizing that they have in fact tripled the recommended dosage of codeine. Research shows that pharmacy users used between 2 and 17 different pharmacies per year to obtain prescription medications. In the current healthcare system we do not have national sector-wide database, which would inform pharmacists at the point of dispensing, of the potential overuse, misuse, abuse or duplication of a product recently dispensed to or currently used by a patient. HENCE the CCI

https://www.samrc.ac.za/reports/SADHS2016 - South Africa Demographic and Health Survey 2016; https://www.ncbi.nlm.nih.gov/pubmed/24091483

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Rationale for OTC use

Patient manage self-limiting colds and coughs without consulting a doctor
Alleviate pressure on healthcare facilities
BUT – responsible use crucial

Act 101 of 1965 as amended – published 26 May, 2017 in the Government Gazette 40869

Section 27(1)(a) of the Constitution provides equal right of people to access healthcare services

Codeine Care Initiative – Legal framework

Accessibility of OTC medicines empowers patients to manage self-limiting conditions without needing to consult a doctor. OTC availability can alleviate pressure on healthcare facilities by allowing self-management especially in resource constraint countries such as South Africa. Responsible use is therefore crucial to prevent misuse and dependence. As a result of the 2017 regulations, the legal framework is now in place to implement a Codeine Care Initiative that has more teeth, Under the 2017 regulations, Schedule 2 codeine-containing products must be combined with other substances like paracetamol. Thus in patients who abuse the medicines are also at risk of complications associated with the other APIs such as liver failure with paracetamol and gastric perforation with NSAIDs Codeine-containing products are scheduled 2 to 6 depending on the dose and whether they contain additional active ingredients.

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Well absorbed from the GIT
First-pass metabolism via CYP2D6
Active metabolite morphine + metabolites nor-codeine and codeine-6-glucuronide
Crosses the BBB
Binds to mu-opioid receptors in the CNS
Eliminated by the kidneys

Pharmacology

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Indications of Codeine-containing Medicines

Associated malaise, fever and congestion of the nasal sinus and eustachian tube mucosa,

including the symptomatic relief of hay fever, influenza and the common cold

Temporary relief of cough in combination with, for example, Triprolidine hydrochloride, Guaiphenesin, Pseudoephedrine hydrochloride, Diphenhydramine hydrochloride, Ammonium chloride

Combination Cold medicine

Alleviation of Cough

For some formulations - Not be used in children < 12 years & cough syrups from 2 years of age in some cases

Restricted Use

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Warnings and Special Precautions

Adrenal insufficiency

Nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure

Androgen deficiency

Low libido, impotence, erectile dysfunction, amenorrhea, or infertility

Serotonin syndrome

from concomitant administration of serotonergic medicines

Sleep-related breathing disorders - sleep apnoea syndromes, hypoxia

Hyperalgesia - unexplained increase in pain

Risk of Death - ultra-rapid metabolisers of codeine

Compromised respiratory function – Asthma, COPD, lung disease, pulmonary oedema

Impaired Liver function – Reduce dosages in elderly

A well known side effect of codeine is constipation and as such can not be used in patients with obstructive bowel disorders.

Other important warnings and precautions to take note of include:

o Adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

o Androgen deficiency, which may present with non-specific symptoms and signs such as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

o Serotonin syndrome, a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic medicines (see section 4.5). Instruct patients to inform their health care provider if they are taking, or plan to take serotonergic medications.

o Sleep-related breathing disorders such as sleep apnoea syndromes (including central sleep apnoea (SA)) and hypoxia (including sleep-related hypoxia).

o Hyperalgesia may occur with the use of opioids, particularly at high doses. An unexplained increase in pain, or increased levels of pain can occur with increasing opioid dosages.

o Risk of death in ultra-rapid metabolisers of codeine: These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels - Even at labelled dosage regimens, ultra-rapid metabolisers of codeine may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing)

o Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolisers of codeine

In addition it should be used with caution in patients with convulsive disorders, head injuries, and in conditions in which intracranial pressure is raised, compromised respiratory function, such as bronchial asthma, pulmonary oedema, obstructive airways disease, acute respiratory depression, severe lung disease, obesity, obstructive sleep apnoea and in patients at risk of paralytic ileus. patients with hypothyroidism, adrenocortical insufficiency, impaired liver function, prostatic hypertrophy

The dosage should be reduced in elderly and debilitated patients. discontinued and quick medical attention should be sought at the earliest sign of codeine toxicity including symptoms such as extreme sleepiness, confusion, or shallow breathing, which may be life threatening.

Codeine containing products should be discontinued and quick medical attention should be sought at the earliest sign of codeine toxicity including symptoms such as extreme sleepiness, confusion, or shallow breathing, which may be life threatening.

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Sold under personal supervision of a pharmacist
May not be kept in an open shop
Must be recorded in a prescription book
May not to be sold to anyone younger than 12, without prescription
Syrup with codeine sold in 100ml bottles as S2, is no longer considered S2 is > 100ml is sold

Regulatory Requirements

Schedule 2 medicines may only be sold under personal supervision of a pharmacist and may not be kept in an open shop. Every sale of a schedule 2 medicine must be recorded in a prescription book, thus ensuring the pharmacy has details of patients to whom the medicines are sold.

Schedule 2 medicines are not to be sold to anyone younger than 12, unless there is a prescription issued by a registered medical practitioner.

She adds: “Furthermore, the Medicine Act has scheduling regulations, which are used to ‘schedule’ a medicine when registered with the SAHPRA. In these regulations, products containing codeine are allowed to be sold as schedule 2 medicines in the permissible quantities.”

Cough syrup with codeine is sold in 100ml bottles. When more than 100ml is sold, it is no longer considered a schedule 2 medicine and the higher volume may not be sold without a prescription. This, in effect, implies that a pharmacy may not sell more than one bottle of 100ml cough syrup with codeine to a patient without a valid prescription,” Singh says.

influenza and the common cold. As healthcare professionals we have to consider the treatment of the whole person, taking into account mental and social factors, rather than just the symptoms of an illness.

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Thank You

Codeine Controversy: Exploring Its Place in Cold Treatment / Dr Machel Leuschner

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Thank You

Codeine Controversy: Exploring Its Place in Cold Treatment / Dr Machel Leuschner

Codeine is a prodrug metabolized by cytochrome P450 2D6 to morphine which mediates most of the analgesic effects of codeine in the body. Over 100 variants of this enzyme (CYP2D6) result in a continuum of activity. The effects of codeine are primarily dictated by the specific subtype (ultrafast metabolizers vs poor metabolizers) of the polymorphic enzyme CYP2D6 present within the individual.[13]

Ultra-rapid metabolizers can have high concentrations of morphine following the administration of codeine. About 3% of African-Americans, 1% to 10% of the White population, and 11% to 30% of North Africans are ultra-rapid metabolizers.[1] Children who are ultrarapid metabolizers have died following the administration of codeine.[14]

Opioid-induced infant deaths have occurred from breastfeeding by mothers who were ultrarapid metabolizers taking codeine postpartum. Conversely, poor metabolizers may experience poor pain relief when treated with codeine. The presence of the methyl group on the number 3 carbon limits the first-pass presystemic metabolism of codeine in the liver. This increases the availability of codeine following oral administration. The difference between the oral and parental doses of codeine is much smaller than that of other opioids like morphine.[2]

Absorption: Codeine is absorbed from the gastrointestinal tract almost completely (94%), and maximum plasma concentration (Cmax) is achieved after 1 hour.[14] Administration of codeine every 4 hours results in steady-state concentration in 48 hours. Most foods do not significantly affect the absorption of codeine.

Distribution: Codeine has an apparent volume of distribution of 3 to 6 L/kg, suggesting extensive tissue distribution.

Metabolism: Codeine is metabolized by conjugation to morphine (5% to 10%) and N-demethylation to norcodeine (approximately 10%). CYP2D6 is the principal enzyme responsible for transforming codeine to morphine, and P450 3A4 (CYP3A4) is the major enzyme for converting codeine to norcodeine.[14] CYP2D6 inhibitors (for instance, bupropion, fluoxetine, paroxetine, and quinidine) can lead to a decreased level of morphine from codeine metabolism and decrease the analgesic effect following treatment with codeine. Concomitant use with CYP3A4 inhibitors (for instance, macrolide antibiotics, protease inhibitors, and azole antifungal agents) can increase metabolism through the CYP2D6 pathway and thus increase the availability of morphine from treatment with codeine. Conversely, concomitant use with CYP3A4 inducers (for instance, carbamazepine, phenytoin, and rifampicin) can increase norcodeine levels and lower levels of morphine byproduct. Codeine exhibits first-order kinetics in that its rate of metabolism is proportional to the concentration of drug available in plasma.[15] Codeine 6 glucuronide may also cause analgesia. Due to differences in metabolism, the analgesic effects can vary from one individual to another.

Excretion: Approximately 90% of codeine is excreted by the kidney, of which approximately 10% is unchanged. The t½ of codeine and its metabolites is about 3 hours.

Pharmacodynamics: Classically, 3 main opioid receptors are recognized, although other subtypes exist. These are all G-protein coupled and originally named mu, delta, and kappa.[16] When opioids bind to these receptors, a series of intracellular events occur, resulting in decreased intracellular cAMP, hyperpolarization of the cell and neuronal cells, and inhibition of the release of nociceptive neurotransmitters.

Within the nervous system, activation of mu receptors in the midbrain is the dominant mechanism of opioid-induced analgesia. The cough reflex is primarily mediated through the opioid receptors in the medulla and, as such, easily explains the anti-tussive effects of codeine.[17]

Pharmacogenomic considerations (box warning): Patients who are ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism gene (ultrarapid metabolizers) can metabolize codeine to morphine rapidly. Consequently, with standard doses of codeine, these patients may experience the symptoms of opioid overdose. Hence the FDA drug label for codeine reports that individuals who are ultrarapid metabolizers may have life-threatening or fatal respiratory depression at a therapeutic dose.[21]

Although considerable heterogeneity exists concerning CYP2D6 enzyme capability within all ethnicities, Hispanic and White patients exhibit the highest CYP2D6 "ultrafast metabolizer" functionality.[21]

Before making any recommendations, pharmacists should always evaluate a patient’s allergy and medical history and medication profile to screen for contraindications or interactions and tailor recommendations accordingly. During counseling, pharmacists should also inform patients that they should always read labels prior to administration to ensure accurate dosing and to understand the frequency of administration and recommended duration of use, particularly if they are using multiple products, to avoid excessive dosing, therapeutic duplications, and unnecessary drug use.

During counseling, pharmacists should also inform patients that in 2008, the FDA recommended that children younger than 2 years not use OTC cold and cough medications because of concerns about efficacy and safety, and soon after, manufacturers voluntarily relabeled these medications for children 4 years and older.^3,4 Moreover, the American Academy of Pediatrics recommends avoiding cold and cough medications in children younger than 6 years.³ Remind parents and caregivers to use only those OTC products manufactured specifically for children and when in doubt, regarding the appropriateness or dose of the medication, consult a pediatrician or pharmacist. Moreover, remind parents and caregivers to always use calibrated drug measuring devices provided with the selected OTC products when administering liquid medications and to read all labels prior to administering medications to children to ensure proper accuracy and dosage.

Always encourage patients with other comorbidities and/or who are taking other medications to discuss the use of OTC cold, cough, and influenza medications with their primary health care providers to ascertain appropriateness of use.