Buprenorphine

Registered South African indications:

• Treatment of chronic musculoskeletal pain of the joints and the lower back, when that pain is of moderate to severe intensity sufficient to require an opioid to obtain adequate analgesia

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Previous history of application site reactions, suggestive of contact dermatitis with buprenorphine transdermal patches
• Delirium tremens
• Severe hepatic impairment
• Myasthenia gravis
• Should not be used in patients with head injury, intracranial lesions or increased intracranial pressure, shock or a reduced level of consciousness of uncertain origin

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Elderly
• Impaired respiratory function
• Patients concurrently receiving serotonergic agents, including monoamine oxidase inhibitors (MAOIs) or who have received MAOIs within the previous two weeks
• Patients with constipation
• Patients suffering from sleep apnoea
• History of seizure disorder (may lower the seizure threshold in these patients)
• Severe febrile illness (may increase the rate of buprenorphine absorption)

Respiratory depression

• The primary risk of opioid excess is respiratory depression

Sleep-related breathing disorders

• Opioids may cause sleep-related breathing disorders, including central sleep apnoea (CSA) and sleep-related hypoxaemia
• Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of pre-existing sleep apnoea
• In patients who present with CSA, consider decreasing the total opioid dosage

CNS depressants co-administration

• Concomitant use of buprenorphine and sedative medicines such as benzodiazepines or related medicines may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible
• If a decision is made to prescribe opioids concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. It is unknown if such severity can be expected from transdermal formulations of buprenorphine
• The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms

Serotonin syndrome

• There is a risk of serotonin syndrome when buprenorphine is taken with other serotonergic medicines, such as monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs), or tricyclic antidepressants
• This can be a potentially life-threatening condition. Patients who have taken MAOIs in the last two weeks are at higher risk. Careful monitoring is advised, particularly when starting treatment or increasing the dose. Symptoms can include changes in mental state, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms

Medicine dependence, tolerance, and potential for abuse

• Prolonged use of buprenorphine can lead to medicine dependence, even at prescribed doses. The risk is higher for individuals with a history of substance misuse, including alcohol, or mental health disorders like major depression
• With chronic use, patients may develop tolerance, and they may feel the need to increase the dose or take other pain relievers
• Overuse or misuse can lead to overdose and death. This risk is increased when buprenorphine is taken with other substances, such as benzodiazepines or ethanol. Patients with a history of drug or alcohol abuse or serious mental illness should be prescribed this medication with caution
• Patients should be monitored regularly for signs of misuse, abuse, or addiction

Medicine withdrawal syndrome

• Abruptly stopping or reducing the dose of buprenorphine can cause a withdrawal syndrome. It is important to discuss a tapering strategy before starting treatment
• Withdrawal symptoms are typically mild, start after about two days, and can last for up to two weeks. Common symptoms include restlessness, runny nose, yawning, sweating, chills, and muscle aches. Other symptoms may include irritability, anxiety, insomnia, nausea, and diarrhoea
• If a woman takes this medicine during pregnancy, her newborn baby may experience neonatal withdrawal syndrome

Hyperalgesia

• Hyperalgesia, or increased sensitivity to pain, may occur with long-term opioid use. This pain is often more widespread and less defined than the original pain
• It is different from pain caused by disease progression or tolerance. Hyperalgesia symptoms may improve by reducing the dose of the opioid
• Buprenorphine should not be used at doses higher than recommended

Skin reactions at the application site

• Following the instructions for use is important to minimise the risk of skin reactions
• Irritant contact dermatitis can occur, causing mild to moderate inflammation at the application site. Symptoms typically include redness, swelling, itching, rash, or a burning sensation. These reactions usually resolve on their own after the buprenorphine patch is removed
• The patch can also cause a delayed allergic reaction called allergic contact dermatitis. This can present with symptoms similar to irritation but may be more severe, including blistering, and may spread beyond the application site. If allergic contact dermatitis is suspected, the patch should be discontinued to prevent complications like ulceration and infection
• Patients and caregivers should be instructed to monitor the application site for any signs of these reactions

Endocrine system

• Opioids may affect the hypothalamic-pituitary-adrenal or -gonadal axes, which can lead to changes in hormone levels, such as an increase in prolactin and a decrease in cortisol and testosterone

Post-operative period

• Buprenorphine is not recommended for pain relief immediately after surgery or in other situations where the need for pain relief changes quickly

Abstinence syndrome precautuions

• Buprenorphine can cause euphoria and physical dependence. Administering buprenorphine to a person who is physically dependent on full µ-opioid agonists may precipitate an abstinence syndrome

Effects on ability to drive and use machines

• Buprenorphine may impair the ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: pat

South African registered indications and dosages

Treatment of chronic musculoskeletal pain of the joints and the lower back, when that pain is of moderate to severe intensity sufficient to require an opioid to obtain adequate analgesia

• Transdermal (pat): Initial: 5μg/hr patch, applied once every 7 days; Titration: During the titration process, the dose may be adjusted every 3 days (72hrs); Thereafter, the 7-day dosing interval should be maintained; Changes in dosage may be individually titrated based on need for supplemental analgesia and the patient’s analgesic response to buprenorphine; To increase the dose, a larger patch should replace the patch that is currently being worn, or a combination of patches should be applied in different places to achieve the desired dose; It is recommended that no more than two patches be applied at the same time, regardless of patch strength; Titration should continue every 3-7 days until adequate analgesia is achieved; If adequate pain control cannot be achieved, therapy with buprenorphine should be discontinued and the patient converted to an appropriate analgesic regimen

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The lowest buprenorphine dose available, 5µg/hr should be used as the initial dose in all patients

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During initiation, titration, and treatment with buprenorphine, patients may continue their existing NSAID or paracetamol regimen as needed

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Discontinuation
After removal, plasma concentrations decrease gradually. This should be considered when therapy with buprenorphine is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of the buprenorphine transdermal patch

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See additional prescribing points for method of administration and application directions

Not established for use in children below 18 years  

Pregnancy

South African recommendations

• Caution; not recommended
• Buprenorphine should not be used during pregnancy
• Buprenorphine has been shown to cross the placenta in humans. Prolonged used of buprenorphine during pregnancy can result in neonatal opioid withdrawal syndrome

Breastfeeding

South African recommendations

• Caution; not recommended
• Buprenorphine should not be used during lactation
• Buprenorphine has been detected in newborn blood, urine and meconium and also in mother’s milk at low concentrations

Fertility

South African recommendations

• No human data on the effect of buprenorphine on fertility are available. In animal studies, no effect on fertility has been observed with buprenorphine

South African recommendations

• No dosage adjustment recommended

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Contraindicated
  Patients with severe hepatic impairment may accumulate buprenorphine during treatment. Buprenorphine should not be used in such patients

South African recommendations

• Caution; no information available

Immune System Disorders

Uncommon

• Allergic reaction (including oropharyngeal swelling and swollen tongue)

Very rare

• Anaphylactic response

Metabolism and Nutrition Disorders

Common

• Anorexia

Rare

• Dehydration*

Psychiatric Disorders

Common

• Confusional state
• Depression*
• Insomnia
• Nervousness
• Anxiety

Uncommon

• Affect lability
• Agitation
• Euphoric mood
• Hallucination
• Decreased libido
• Nightmare
• Aggression

Rare

• Psychotic disorder

Very rare

• Depersonalisation
• Medicine dependence

Nervous System Disorders

Very common

• Dizziness
• Headache*
• Somnolence*

Common

• Tremor

Uncommon

• Concentration impairment
• Abnormal co-ordination
• Dysarthria
• Dysgeusia
• Hypoaesthesia
• Memory impairment
• Migraine
• Syncope*
• Paraesthesia

Very rare

• Convulsions

Not known

• Hyperalgesia
• Sleep apnoea syndrome

Eye Disorders

Uncommon

• Dry eye
• Blurred vision

Rare

• Miosis

Ear and Labyrinth Disorders

Uncommon

• Tinnitus
• Vertigo

Cardiac Disorders

Uncommon

• Palpitations
• Tachycardia

Rare

• Angina pectoris

Vascular Disorders

Uncommon

• Flushing
• Hypertension*

Rare

• Vasodilatation
• Orthostatic hypotension

Very rare

• Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Common

• Dyspnoea*

Uncommon

• Cough
• Hiccups
• Wheezing

Rare

• Asthma aggravated*
• Hyperventilation
• Hypoxia
• Respiratory failure
• Rhinitis

Very rare

• Respiratory depression

Gastrointestinal Disorders

Very common

• Constipation*
• Nausea*
• Vomiting*

Common

• Abdominal pain*
• Diarrhoea*
• Dry mouth
• Dyspepsia*

Uncommon

• Flatulence

Rare

• Dysphagia
• Ileus

Not known

• Diverticulitis*

Hepatobiliary Disorders

Not known

• Biliary colic*

Skin and Subcutaneous Tissue Disorders

Very common

• Pruritus*

Common

• Rash*
• Sweating*

Uncommon

• Dry skin
• Urticaria
• Dermatitis contact

Rare

• Face oedema

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Muscle spasm
• Myalgia

Renal and Urinary Disorders

Uncommon

• Urinary incontinence
• Urinary retention
• Urinary hesitation

Reproductive System and Breast Disorders

Rare

• Sexual dysfunction

General Disorders and Administration Site Conditions

Very common

• Application site reaction^†

Common

• Asthenic conditions (including muscle weakness)
• Peripheral oedema

Uncommon

• Oedema
• Pyrexia*
• Rigors*
• Withdrawal syndrome
• Chest pain
• Application site dermatitis**

Rare

• Influenza-like illness

Not known

• Withdrawal syndrome neonatal
• Tolerance

Investigations

Uncommon

• Alanine amino-transferase increased
• Weight decreased

Injury and Poisoning

Uncommon

• Accidental injury (including fall)

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* At least one serious case
^† Includes: application site erythema, application site oedema, application site pruritus, application site rash
** In some cases late onset local allergic reactions occurred with marked signs of inflammation. In such cases treatment with buprenorphine should be terminated

Adverse Events identified through Post-marketing Experience

Gastrointestinal Disorders

Rare

• Increased risk of abdominal pain, including pancreatitis has been reported

Description of Selected Adverse Reactions

• Mechanical injuries during patch removal (e.g. laceration) are also possible in patients with fragile skin
• Chronic inflammation may lead to long-lasting sequelae, such as post inflammatory hyper- and hypopigmentation, as well as dry and thick scaly skin lesions, which may closely resemble scars. In such cases treatment with buprenorphine should be terminated (see Contraindications and; Warnings and Precautions)
• After discontinuation of buprenorphine, withdrawal symptoms are uncommon. This may be due to the very slow dissociation of buprenorphine from the opioid receptors and to the gradual decrease of buprenorphine plasma concentrations (usually over a period of 30 hours after removal of the last patch)

• Monoamine oxidase inhibitors
• CYP3A4 inhibitors
• CYP3A4  inducers
• General anaesthetics
• Other medicinal agents which reduce hepatic blood flow
• Warfarin
• Alcohol
• Central nervous system depressants  

None routine. Specific cases may require 

• Vital signs
• Hepatic function

Method of administration

• In order to minimise the potential of skin reactions, the buprenorphine transdermal patch should be applied to non-irritated, intact skin of the upper outer arm, upper chest, upper back or the side of the chest
• Apply to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven
• Application sites should be rotated whenever a transdermal patch is replaced or added. Application sites should be re-used at no less than 3-week intervals. If the application site must be cleaned, it should be done with clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. The skin must be dry before the transdermal patch is applied
• The patch should be pressed firmly in place at the application site, making sure contact is complete, especially around the edges. If the edges of the patch begin to peel off, the edges may be taped down with suitable skin tape. If a transdermal patch falls off, a new one should be applied
• Bathing, showering, or swimming should not affect the system. While wearing the patch, patients should be advised to avoid exposing the patch site to direct external heat sources such as heating pads, electric blankets, heat lamps, hot water bottles etc., as an increase in absorption of buprenorphine may occur. The effects of the use of buprenorphine patch system in hot tubs and saunas have not been studied

Application directions

• Open the pouch just before applying the patch by cutting the pouch along the dotted line with scissors. Be careful not to damage the transdermal patches with the scissors. Take off the thin cover sheet
• Attach the patch to the upper arm, upper chest, upper back, or sides of the chest
• Press the patch with the hand for approximately 30 seconds and check that it is properly attached. The patch should not be used if the seal is broken

Buprenorphine is an opioid analgesic that is an agonist to the µ-opioid receptor and an antagonist at the kappa-opioid receptor.

Transdermal Patch 5μg

• Sovenor (Mundipharma) originator

Transdermal Patch 10μg

• Sovenor (Mundipharma) originator

Transdermal Patch 20μg

• Sovenor (Mundipharma) originator

Also available in the following form: Tablet and injection.