Nalbuphine Hydrochloride

Registered South African indications:

• Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate
• Supplement to balanced anaesthesia, for preoperative and postoperative analgesia
• Obstetrical analgesia during labour and delivery

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Limitations of use
Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses, reserve nalbuphine for use in patients for whom alternative treatment options (e.g., non-opioid analgesics):
- Have not been tolerated, or are not expected to be tolerated,
- Have not provided adequate analgesia or are not expected to provide adequate analgesia

LIFE-THREATENING RESPIRATORY DEPRESSION and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Life threatening respiratory depression: Serious, life-threatening, or fatal respiratory depression may occur with use of nalbuphine, particularly when used concomitantly with other opioids or central nervous system depressants. Monitor for respiratory depression, especially during initiation of nalbuphine or following a dose increase. Risks from concomitant use with benzodiazepines or other central nervous system depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death Reserve concomitant prescribing of nalbuphine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate Limit dosages and durations to the minimum required Follow patients for signs and symptoms of respiratory depression and sedation

Registered South African contraindications

• Hypersensitivity to the active ingredient or to any of its excipients
• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Life-threatening respiratory depression

• Serious, life-threatening, or fatal respiratory depression has been reported with opioid use, including when used as recommended
• Respiratory depression may lead to respiratory arrest and death if not promptly recognised and treated
• Management may include close monitoring, supportive care, and the use of opioid antagonists depending on clinical status
• CO₂ retention from opioid-induced respiratory depression may worsen sedation

Monitoring during initiation and titration

• The risk of respiratory depression is highest during therapy initiation or dose increases
• Patients should be closely monitored, especially within the first 24 to 72 hours of starting nalbuphine or after a dose increase

Importance of proper dosing

• To minimise risk of respiratory depression, correct dosing and titration of nalbuphine is essential
• Overestimation of dose during opioid conversion may result in fatal overdose with the first dose

Sleep-related breathing disorders

• Opioids can cause central sleep apnoea (CSA) and sleep-related hypoxemia
• Risk of CSA increases in a dose-dependent manner
• In patients presenting with CSA, consider tapering the opioid dose using best practices for opioid taper

Concomitant use with benzodiazepines or other CNS depressants

• Profound sedation, respiratory depression, coma, and death may result from concomitant use of nalbuphine with benzodiazepines or other CNS depressants (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anaesthetics, antipsychotics, other opioids, alcohol)
• Reserve combined use for patients with inadequate alternative treatment options
• Prescribe the lowest effective doses and shortest duration of concomitant use
• Titrate carefully and monitor closely for sedation and respiratory depression
• Advise patients and caregivers about the risks and to avoid activities requiring mental alertness
• Screen patients for substance use disorders and warn of overdose risk when using additional CNS depressants, including alcohol and illicit substances

Use in patients with chronic pulmonary disease

• Nalbuphine is contraindicated in patients with acute or severe bronchial asthma in unmonitored settings
• Patients with significant COPD, cor pulmonale, and substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of reduced respiratory drive, including apnoea, even at recommended doses

Use in elderly, cachectic, or debilitated patients

• Life-threatening respiratory depression is more likely due to altered pharmacokinetics or clearance
• Monitor closely during initiation, titration, and concomitant use with other respiratory depressants
• Consider non-opioid analgesics as alternatives where appropriate

Adrenal insufficiency

• Cases of adrenal insufficiency have been reported with opioid use, typically after more than one month
• Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure
• Confirm diagnosis through appropriate testing and treat with physiologic doses of corticosteroids
• Taper off nalbuphine to allow adrenal function to recover; another opioid may be tried if necessary

Severe hypotension

• Nalbuphine may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients
• Risk is higher in patients with reduced blood volume or those on CNS depressants (e.g. phenothiazines, general anaesthetics)
• Monitor for signs of hypotension during initiation and titration
• Avoid use in patients with circulatory shock, as nalbuphine may cause vasodilation and further reduce cardiac output and blood pressure

Increased intracranial pressure or head injury or impaired consciousness

• In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumours), nalbuphine may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure
• Monitor for sedation and respiratory depression in patients with brain tumours, head injury, or increased intracranial pressure
• Avoid use in patients with impaired consciousness or coma
• Nalbuphine may obscure the clinical course in head injury

Gastrointestinal conditions

• Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus
• May cause spasm of the sphincter of Oddi and elevate serum amylase levels
• Monitor patients with biliary tract disease, including pancreatitis, for worsening symptoms

Seizure risk

• Nalbuphine may increase seizure frequency in patients with seizure disorders
• Monitor for worsened seizure control during therapy

Withdrawal risk

• Concomitant use with full opioid agonists may reduce analgesic effect or precipitate withdrawal
• Avoid co-use with full opioid agonist analgesics
• Taper gradually to discontinue in physically dependent patients; do not abruptly stop

Addiction, abuse, and misuse

• Nalbuphine, as an opioid, carries risk of addiction, abuse, and misuse
• Addiction can occur even at recommended doses
• Assess each patient’s risk, especially those with a personal or family history of substance use disorder or mental illness
• Reduce risk by prescribing the smallest effective quantity and monitoring for signs of misuse

• The potential for these risks should not, however, prevent the proper management of pain in any given patient

Myocardial infarction

• Use nalbuphine with caution in patients experiencing myocardial infarction who present with nausea or vomiting

Cardiovascular system

• A higher incidence of bradycardia has been reported during anaesthesia in patients not premedicated with atropine

Laboratory tests

• Nalbuphine may interfere with enzymatic opioid detection methods; consult test manufacturer for details

Serotonin syndrome

• Nalbuphine may cause serotonin syndrome when used with serotonergic medicines
• Patients should be informed of symptoms and advised to seek immediate medical attention if they develop
• Advise patients to inform their healthcare providers if they are taking or plan to take serotonergic medicines

Monoamine Oxidase Inhibitor (MAOI) interaction

• Patients should avoid taking nalbuphine while using monoamine oxidase inhibitors (MAOIs)
• Do not initiate MAOIs during treatment with nalbuphine

Constipation

• Nalbuphine may cause severe constipation
• Patients should be advised on constipation management and when to seek medical attention

Use in children

• Safety and effectiveness of nalbuphine have not been established in paediatric patients under 18 years of age

Effects on ability to drive and use machines

• Nalbuphine may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Patients should not drive or operate dangerous machinery when they are feeling drowsy or dizzy

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

South African registered indications and dosages

Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate
Obstetrical analgesia during labour and delivery

• IV/IM/SC: Usual recommended dose: 70kg patient: 10mg; Repeat every 3 to 6 hours, as necessary; Dosage should be adjusted according to the severity of the pain, physical status of the patient, and other medicines which the patient may be receiving; In non-tolerant individuals, the recommended single max. dose is 20mg; Max: 160mg/24hrs

Supplement to balanced anaesthesia, for preoperative and postoperative analgesia

The use of nalbuphine as a supplement to balanced anaesthesia requires larger doses than those recommended for analgesia

• IV: Induction dose: Range from 0.3mg/kg to 3mg/kg body weight admin. over 10-15min; Maintenance: 0.25 to 0.5mg/kg body weight as single IV admin. as required; The use of nalbuphine may be followed by respiratory depression which can be reversed with the opioid antagonist naloxone hydrochloride

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Limitations of use
Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses, reserve nalbuphine for use in patients for whom alternative treatment options (e.g. non-opioid analgesics):
- Have not been tolerated, or are not expected to be tolerated,
- Have not provided adequate analgesia or are not expected to provide adequate analgesia

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Nalbuphine should be administered as a supplement to general anaesthesia only by medical practitioners trained in the use of intravenous anaesthetics and management of the respiratory effects of potent opioids. Naloxone, resuscitative and intubation equipment, and oxygen should be readily available. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

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Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with nalbuphine and adjust the dosage accordingly

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Nalbuphine should be inspected visually for particulate matter and discolouration prior to administration whenever the solution and container permit

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See additional prescribing points for more details on titration, maintenance and discontinuation of therapy

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Use in pregnancy (other than labour): Caution; not recommended
• Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with nalbuphine in pregnant women are insufficient to inform a medicine-associated risk for major birth defects and miscarriage

Clinical considerations - Foetal/neonatal adverse reactions

• Severe foetal bradycardia has been reported when nalbuphine is administered during labour. Naloxone may reverse these effects. Although there are no reports of foetal bradycardia earlier in pregnancy, it is possible that this may occur. Therefore, the use of nalbuphine in pregnant women should be avoided
• Nalbuphine should be used in pregnancy only if clearly needed and if appropriate measures such as foetal monitoring are taken to detect and manage any potential adverse effect on the foetus

Labour and delivery

• The placental transfer of nalbuphine is high, rapid, and variable with a maternal to foetal ratio ranging from 1:0.37 to 1:6
• Foetal and neonatal adverse effects that have been reported following the administration of nalbuphine to the mother during labour include foetal bradycardia, respiratory depression at birth, apnoea, cyanosis, and hypotonia. Some of these events have been life-threatening
• Maternal administration of naloxone during labour has normalised these effects in some cases. Severe and prolonged foetal bradycardia has been reported. Permanent neurological damage attributed to foetal bradycardia has occurred. A sinusoidal foetal heart rate pattern associated with the use of nalbuphine has also been reported
• Nalbuphine should be used during labour and delivery only if clearly indicated. Newborns should be monitored for respiratory depression, apnoea, bradycardia, excess sedation and dysrhythmias if nalbuphine has been used
• Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate
• Nalbuphine is not recommended for use in pregnant women during or immediately prior to labour, when other analgesic techniques are more appropriate
• Opioid analgesics, including nalbuphine, can prolong labour through actions which temporarily reduce the strength, duration, and frequency of uterine contractions

Breastfeeding

South African recommendations

• Caution
• Limited data suggest that nalbuphine is excreted in maternal milk but only in a small amount (less than 1 % of the administered dose). Infants exposed to nalbuphine through breast milk should be monitored for excess sedation and respiratory depression
• Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped

Fertility

South African recommendations

• Animal studies showed no adverse effects on either male or female fertility

South African recommendations

• Caution; dose adjustment recommended
  Because nalbuphine is excreted by the kidneys, nalbuphine should be used with caution in patients with renal dysfunction and administered in reduced amounts

South African recommendations

• Caution; dose adjustment recommended 
  Because nalbuphine is metabolised in the liver, patients with liver dysfunction may show an exaggerated response to customary doses. In these individuals, nalbuphine should be used with caution and administered in reduced amounts

South African recommendations

• Caution; dose adjustment recommended
  Elderly patients (aged 65 years or older) may have increased sensitivity to nalbuphine
  In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy
  Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of nalbuphine slowly in geriatric patients
  Nalbuphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this medicine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function

Immune System Disorders

Less frequent

• Anaphylactic/anaphylactoid and other serious hypersensitivity reactions, including (some reactions may be life-threatening):
  • Shock
  • Respiratory distress
  • Respiratory arrest
  • Bradycardia
  • Cardiac arrest
  • Hypotension
  • Laryngeal oedema
• Other allergic-type reactions reported include:
  • Stridor
  • Bronchospasm
  • Wheezing
  • Oedema
  • Rash
  • Pruritus
  • Nausea and vomiting
  • Diaphoresis
  • Weakness
  • Shakiness

Psychiatric Disorders

Frequent

• Sedation
• Dizziness

Less frequent

• Nervousness
• Depression
• Restlessness
• Crying
• Euphoria
• Floating
• Hostility
• Unusual dreams
• Confusion
• Faintness
• Hallucinations
• Dysphoria
• Feeling of heaviness
• Numbness
• Tingling
• Unreality

Frequency unknown

• Depressed level or loss of consciousness
• Somnolence
• Tremor
• Anxiety
• Agitation
• Seizures

Nervous System Disorders

Frequent

• Sweating or clammy
• Headache

Less frequent

• Speech difficulty

Eye Disorders

Less frequent

• Blurred vision

Ear Disorders

Frequent

• Vertigo

Cardiac Disorders

Less frequent

• Hypertension
• Hypotension
• Bradycardia
• Tachycardia

Vascular Disorders

Less frequent

• Flushing and warmth

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory depression
• Dyspnoea
• Asthma

Frequency unknown

• Pulmonary oedema

Gastrointestinal Disorders

Frequent

• Nausea or vomiting
• Dry mouth

Less frequent

• Cramps
• Dyspepsia
• Bitter taste

Frequency unknown

• Abdominal pain

Skin and Subcutaneous Tissue Disorders

Less frequent

• Itching
• Burning
• Urticaria

Renal and Urinary Disorders

Less frequent

• Urinary urgency

General Disorders and Administration Site Conditions

Frequency unknown

• Pyrexia
• Injection site reactions such as:
  • Pain
  • Swelling
  • Redness
  • Burning, and hot sensations

• Benzodiazepines
• Other opioid analgesics
• Other central nervous system (CNS) depressants
• Other sedatives/hypnotics
• Anxiolytics
• Tranquilizers
• Muscle relaxants
• General anaesthetics
• Antipsychotics
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin and norepinephrine reuptake inhibitors (SNRIs)
• Tricyclic antidepressants (TCAs)
• Triptans
• 5- HT3 receptor antagonists
• Medicines that effect the serotonin neurotransmitter system
• Mirtazapine
• Trazodone
• Tramadol
• Certain muscle relaxants
• Cyclobenzaprine
• Metaxalone
• Monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also, others, such as linezolid and intravenous methylene blue)
• Skeletal muscle relaxants
• Diuretics
• Anticholinergic medicines
• Phenelzine
• Tranylcypromine
• Linezolid

Other interactions

• Alcohol

• Blood pressure
• Pain relief
• Sedation
• Respiratory status
• Mental status
• Toxicology status
  • Recommended before initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). Prescription drug monitoring should be reviewed by clinicians before initiation and periodically during therapy (frequency ranging from every prescription to every 3 months)

Additional observations

• Patients with a history of seizures
• Bowel function
• Signs/symptoms of substance use disorder, abuse, or misuse
• Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment)
  • In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy
  • In patients on long-term therapy, reevaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder
• Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases

Titration and maintenance of therapy

• Individually titrate nalbuphine to a dose that provides adequate analgesia and minimizes adverse reactions
• Continually re-evaluate patients receiving nalbuphine to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse
• Frequent communication is important among the doctor, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration
• If the level of pain increases after dosage stabilisation, attempt to identify the source of increased pain before increasing the nalbuphine dosage
• If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse events

Discontinuation of nalbuphine

• When a patient who has been receiving nalbuphine regularly and may be physically dependent no longer requires therapy with nalbuphine, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal
• If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue nalbuphine in a physically dependent patient

Nalbuphine is a potent analgesic that acts as an agonist at kappa opioid receptors and an antagonist at mu (μ) opioid receptors.