Health Canada Advisories

Recall of one lot of pms-Hydromorphone due to packaging error that could potentially lead to overdose (2022-08)
Important Safety Information - Importation of German-labelled Hydromorphon Ethypharm Kalceks (Hydromorphone
Hydrochloride Solution for Injection) due to Potential Shortage of Canadian-labelled HYDROmorphone - JAMP
Pharma Corporation (2021-01)
Prescription Cough and Cold Products Containing Opioids and the Risk of Opioid Use Disorder in Children and
Adolescents (< 18 years of age) (2020-08)
Non-prescription pain relief products containing codeine are not recommended for use in people under 18 years of
age (2020-07)
Health Canada Important Safety Information on Methadone Treatment of Opioid Dependence and Potential Risk of
Lack of Effect when Switching between Different Products (2020-07)

OPIOIDS
buprenorphine—buprenorphine HCl—butorphanol tartrate—codeine monohydrate—codeine
phosphate—codeine sulfate trihydrate—fentanyl—fentanyl citrate—hydrocodone bitartrate—
hydromorphone HCl—methadone HCl—morphine HCl—morphine sulfate—nalbuphine HCl—
normethadone HCl—oxycodone HCl—pentazocine HCl—pentazocine lactate—pethidine HCl—
remifentanil HCl—sufentanil citrate—tapentadol HCl—tramadol HCl
Analgesic
CPhA Monograph

Date of Revision: November 30, 2020

This monograph has been compiled by CPhA and reviewed by experts. It may contain information different
from that found in Health Canada–Approved Product Monographs. The reader is referred to the CPS
Editorial Policy for more information.

Summary Product Information

Route of
Drug​[a] Administration Dosage Form Strength

Buprenorphine Buccal Soluble film 75 mcg, 150 mcg, 300 mcg,

450 mcg, 600 mcg, 750 mcg,
900 mcg

SL Tablet 2 mg in combination with

naloxone 0.5 mg

8 mg in combination with
naloxone 2 mg

Transdermal Patch Delivers 5 mcg, 10 mcg, 15

mcg or 20 mcg/h

Butorphanol Nasal Spray 10 mg/mL

 Route of
Drug​[a] Administration Dosage Form Strength

Codeine Oral​[b] Immediate-release tablet 15 mg, 30 mg

Controlled-release tablet 50 mg, 100 mg, 150 mg, 200

mg

Solution 2 mg/mL

Syrup 5 mg/mL

IM, SC Injectable solution 30 mg/mL

Fentanyl Buccal, sublingual Effervescent tablet 100 mcg, 200 mcg, 400 mcg,
600 mcg, 800 mcg

Sublingual Tablet 100 mcg, 200 mcg, 300 mcg,

400 mcg, 600 mcg, 800 mcg

Transdermal Patch Delivers 12 mcg, 25 mcg, 37

mcg, 50 mcg, 75 mcg or 100
mcg/h

Epidural, IM, IV Injectable solution 50 mcg/mL

Hydrocodone Oral​[c] Immediate-release tablet 5 mg

Oral Syrup 1 mg/mL

Hydromorphone Oral Immediate-release tablet 1 mg, 2 mg, 4 mg, 8 mg

Controlled-release 3 mg, 4.5 mg, 6 mg, 9 mg, 12

capsule mg, 18 mg, 24 mg, 30 mg

Prolonged-release tablet 4 mg, 8 mg, 16 mg, 32 mg

Syrup 1 mg/mL

Rectal Suppository 3 mg

IM, IV, SC Injectable solution 2 mg/mL, 10 mg/mL, 20

mg/mL, 50 mg/mL, 100 mg/mL

Meperidine Oral Immediate-release tablet 50 mg

(pethidine) IV, IM, SC Injectable solution 10 mg/mL, 50 mg/mL

Methadone Oral​[d] Tablet 1 mg, 5 mg, 10 mg, 25 mg

 Route of
Drug​[a] Administration Dosage Form Strength

Solution 1 mg/mL, 10 mg/mL

Morphine Oral Immediate-release tablet 5 mg, 10 mg, 20 mg, 25 mg,

30 mg, 50 mg

Immediate-release 5 mg, 10 mg, 20 mg, 30 mg

capsule

Controlled-release 10 mg, 15 mg, 20 mg, 30 mg,

capsule 50 mg, 60 mg, 100 mg, 200 mg

Extended-release tablet 15 mg, 30 mg, 60 mg, 100 mg,

200 mg

Drops 20 mg/mL, 50 mg/mL

Syrup 1 mg/mL, 5 mg/mL

Rectal Suppository 5 mg, 10 mg, 20 mg, 30 mg

IV, IM, SC Injectable solution 1 mg/mL, 2 mg/mL, 5 mg/mL,

10 mg/mL, 15 mg/mL, 50
mg/mL

Epidural Injectable solution 0.5 mg/mL, 1 mg/mL

Nalbuphine IV, IM, SC Injectable solution 10 mg/mL

Normethadone Oral Oral drops 10 mg/mL in combination with

p-hydroxyephedrine 20 mg/mL

Oxycodone Oral Immediate-release tablet 5 mg, 10 mg, 20 mg

5 mg in combination with ASA

or acetaminophen 325 mg

2.5 mg in combination with

acetaminophen 325 mg

Sustained-release tablet 5 mg, 10 mg, 15 mg, 20 mg,

30 mg, 40 mg, 60 mg, 80 mg

5 mg in combination with
naloxone 2.5 mg

10 mg in combination with
naloxone 5 mg
 Route of
Drug​[a] Administration Dosage Form Strength

20 mg in combination with
naloxone 10 mg

40 mg in combination with
naloxone 20 mg

Rectal Suppository 10 mg, 20 mg

Pentazocine Oral Immediate-release tablet 50 mg

IV, IM, SC Injectable solution 30 mg/mL

Remifentanil IV Powder for solution 1 mg/vial, 2 mg/vial, 5 mg/vial

Sufentanil IV, epidural Injectable solution 50 mcg/mL

Tapentadol Oral Immediate-release tablet 50 mg, 75 mg, 100 mg

Extended-release tablet 50 mg, 100 mg, 150 mg, 200

mg, 250 mg

Tramadol Oral Immediate-release tablet 50 mg

37.5 mg in combination with

acetaminophen 325 mg

Controlled-release tablet 75 mg, 100 mg, 150 mg, 200

mg, 300 mg, 400 mg

Extended-release tablet 100 mg, 200 mg, 300 mg

[a] Alfentanil is no longer available in Canada as of October 2018.

[b] Codeine is also available in various combinations with non-opioid analgesics, caffeine, muscle relaxants, antihistamines,
decongestants, expectorants and/or barbiturates. More information can be found on Health Canada’s Drug Product Database.
[c] Hydrocodone is available as a single ingredient in syrup form as well as in various combinations with antihistamines,
decongestants, and/or expectorants as syrup and suspension. More information can be found on Health Canada’s Drug
Product Database.
[d] Methadone prescribing requires special authorization from Health Canada; see Indications and Clinical Use.

Indications and Clinical Use

Health Canada–Approved Indications

Treatment of pain: different products are used for acute pain, chronic non-cancer pain and cancer pain.
Opioids are generally reserved for pain that does not respond to other treatment options or when other options
are not appropriate. For the treatment of chronic non-cancer pain, 2017 guidelines recommend the use of
opioids only when non-opioid analgesics and nonpharmacological therapy are not effective [The 2017
 Canadian guideline for opioids for chronic non-cancer pain, available from:
www.nationalpaincentre.mcmaster.ca]. Some specific approved indications include:
treatment of postoperative pain: butorphanol nasal spray, epidural sufentanil
adjunct to preoperative and postoperative analgesia and as a supplement to surgical anesthesia:
nalbuphine and pentazocine injections
treatment of pain during labour and delivery: nalbuphine injection
analgesic adjunct to epidural bupivacaine during labour and vaginal delivery: epidural sufentanil
treatment of breakthrough pain in adult cancer patients who are opioid-tolerant, defined as already
receiving at least the opioid equivalent of 60 mg of oral morphine daily for a week or longer: fentanyl
buccal/sublingual tablets
treatment of moderate to severe pain in patients with opioid-related constipation: oxycodone in
combination with naloxone improves bowel function compared with oxycodone alone while providing
analgesia
adjunct to anesthesia: fentanyl, remifentanil, sufentanil
Treatment of nonproductive cough: codeine, hydrocodone, normethadone.
Treatment of opioid use disorder: methadone and buprenorphine are the drugs of choice as opioid agonist
therapy in patients who have an opioid use disorder. Buprenorphine combined with naloxone is first-line
therapy in British Columbia. Slow-release oral morphine may be considered as a third-line option. Detailed
requirements for the prescribing, dispensing, supervision and monitoring of buprenorphine/naloxone therapy
are outlined in the product monograph. Prescribing of buprenorphine/naloxone requires specialized education,
in accordance with the approved product labelling. Physicians and other health professionals should contact
their respective licensing bodies for information on their province’s practice requirements concerning
buprenorphine. The buprenorphine/naloxone combination product is not indicated for the treatment of pain. In
Canada, all physicians prescribing methadone require a federal exemption for pain or addiction. Methadone is
approved for the treatment of opioid use disorder. Physicians who wish to prescribe or administer methadone
must obtain an exemption from the Minister of Health (or designate) at the Office of Controlled Substances,
613-946-5139 or 1-866-358-0453. In British Columbia, Manitoba, Ontario and Quebec, the methadone
program is administered by the respective College of Physicians and Surgeons; after reviewing physicians’
requests, the respective college would recommend to the minister that they be granted an exemption under
section 56 of the Controlled Drugs and Substances Act with respect to methadone. Guidelines have been
developed or endorsed by health professional licensing authorities in some provinces to assist their members
in the prescribing or dispensing of methadone. Practitioners should contact their respective licensing authority
for more information.

Pediatrics
Normethadone and combination products containing hydrocodone are approved for treatment of nonproductive
cough in children ≥6 years of age. However the use of opioid-containing cough or cold products is not
recommended for children and adolescents <18 years of age. For more information, consult the Summary Safety
Review issued by Health Canada.

Uses Without Health Canada Approval

Methadone is used as an analgesic in chronic cancer pain, palliative care and chronic pain disorders. Separate
special authorization is required if the focus of treatment is to relieve pain. See Health Canada–Approved
Indications.

Morphine is used to manage neonatal abstinence syndrome.

Morphine is the drug of choice to manage pain in patients with ST-elevation myocardial infarction [J Am Coll Cardiol
2013;61(4):e78-e140].

Opioids, especially morphine, are first-line agents to manage dyspnea in cancer patients and have been effective in
other types of dyspnea [Cochrane Database Syst Rev 2016;3:CD011008].

Tapentadol extended-release tablets are an alternative for the treatment of diabetic neuropathy in patients who
require continuous pain control and who have not responded to other therapies [Pain Res Manag 2014;19(6):328-
35].

Injectable hydromorphone can be used as a supervised injectable opioid agonist treatment for severe and/or
refractory opioid abuse disorder in patients who have not benefited from oral opioid agonist therapy or who have
been assessed as being at severe risk of overdose death [British Columbia Centre on Substance Use. Guidance for
injectable opioid agonist treatment for opioid use disorder].

Contraindications
See individual product monographs for comprehensive information.

Patients who are hypersensitive to opioids or to any ingredient in the formulation or component of the container.
Opioid-naive patients: buprenorphine/naloxone, fentanyl buccal, sublingual and transdermal patches, oxycodone
doses above 40 mg, and oxycodone/naloxone 40/20 mg controlled-release tablets.
Opioid-dependent patients: opioid agonist-antagonists can precipitate a withdrawal syndrome.
Mild pain that can be treated with non-opioid therapy.
Severe respiratory insufficiency, including acute asthma, chronic obstructive lung disease and upper airway
obstruction.
Central nervous system (CNS) depression, head injury and elevated CSF pressure.
Gastrointestinal obstruction and conditions that affect bowel transit.
Acute appendicitis or pancreatitis.
Seizure disorders.
Myasthenia gravis due to increased risk of respiratory depression if muscle rigidity occurs.
Alcohol: avoid due to increased risk of respiratory and CNS depression.
Substance use disorder: opioids are not recommended for chronic non-cancer pain treatment.
Circulatory shock: opioids can cause vasodilation.
MAO inhibitors: avoid within 14 days.
Oral mucositis: avoid buccal buprenorphine due to possible increased exposure and toxicity.
Severe hepatic impairment: buprenorphine transdermal, buprenorphine/naloxone, oxycodone/naloxone,
tapentadol, tramadol.
Severe renal impairment: oxycodone/naloxone, tapentadol, tramadol.
Codeine is contraindicated in the postoperative management of pain in patients ≤18 years of age following
tonsillectomy and/or adenoidectomy.

Warnings and Precautions

Serious Warnings and Precautions

Opioid use has resulted in addiction, diversion, and both fatal and nonfatal overdoses. Restrict
opioid use to situations where non-opioid analgesics are insufficient for pain control. Chronic
opioid use for non-cancer pain should be considered only after non-opioid analgesic therapy
has been optimized. Restrict initial and maximum doses (see Dosage and Administration). In an
effort to increase patient awareness of these issues, Health Canada has mandated opioid
warning stickers and patient information handouts be provided with every opioid prescription at
the point of sale as of October 2018 [Health Canada. Questions and answers: prescription
opioids—sticker and handout requirements for pharmacists and practitioners].
Opioids should not be used for chronic non-cancer pain in patients with an existing or history of
substance use disorder.
Respiratory depression has been fatal and can occur with any dosage form. Use the lowest
effective dose for the shortest duration. Avoid accidental exposure since even 1 dose can be
 fatal in a child. See Contraindications and Drug Interactions.
Neonatal abstinence syndrome can result from prolonged maternal opioid use during
pregnancy. See Warnings and Precautions, Special Populations, Pregnant Women.
QT interval prolongation with methadone has caused serious arrhythmias. Transdermal and
buccal buprenorphine is not recommended in patients with a history of QT prolongation or
taking class I or III antiarrhythmics. See Drug Interactions.

General
Overdose: Patients at higher risk for serious overdose are those with a history of overdose, a history of substance
abuse, higher opioid doses (>90 mg morphine equivalents daily), or those taking benzodiazepines, gabapentin or
pregabalin. For treatment of acute pain, exposure to opioids may be the 1​st step leading to long-term opioid use
and addiction; therefore, use low doses for a short duration for acute pain. In patients with chronic pain, monitor
regularly and refer for treatment of opioid abuse disorder if needed. One dose can be fatal in a child. Overdose and
death can occur when methadone is ingested by individuals for whom it has not been prescribed or who are not
opioid-dependent. Encourage individuals who are at risk of overdose and their families to obtain a naloxone kit.

Abuse: All opioid agonists and partial agonists have the potential for abuse, misuse and criminal diversion.
Fentanyl and illicitly manufactured, highly potent fentanyl analogs are of particular concern.

Some products are formulated to reduce IV abuse, e.g., oxycodone/naloxone controlled-release tablets contain
excipients (especially talc) that can cause serious toxicity if injected, oxycodone controlled-release tablets (OxyNeo)
resist crushing and dissolving in water, and buprenorphine sublingual tablets include naloxone to deter injection and
intranasal misuse due to its ability to precipitate withdrawal. To store and dispose of opioids properly, see Storage
and Stability.

Withdrawal syndrome will occur if opioids are suddenly discontinued in patients who have been taking them
regularly. Typical symptoms include tachycardia, chills, sweating, restlessness, dilated pupils, bone or joint aches,
diarrhea, tremor, yawning, irritability, anxiety, and runny nose. Tramadol withdrawal syndrome may also include
withdrawal effects from its serotonergic actions, with symptoms of anxiety, delusions, paranoia and hallucinations.

Opioids are on the list of High-Alert Medications by the Institute for Safe Medication Practices (ISMP) Canada, for
which the consequences of an error can be particularly devastating. Special safeguards should be established to
reduce the risk of errors.

Genetic polymorphism in the CYP2D6 enzyme should be considered when prescribing codeine. In CYP2D6 poor
metabolizers, guidelines recommend avoiding codeine due to possible lack of analgesic effect [Clin Pharmacol Ther
2012;91(2):321-6]. In CYP2D6 ultra-rapid metabolizers, avoidance of codeine is recommended due to the risk of
increased toxicity. Tramadol should also be used with caution. See Dosage and Administration, Genetic
Polymorphism, and Action and Clinical Pharmacology, Pharmacokinetics.

Pentazocine can trigger an attack of porphyria in susceptible individuals.

Pentazocine tablets contain sodium metabisulfite, which can cause a reaction in patients sensitive to sulfites.

Cardiovascular
Severe hypotension is more likely in patients with low blood volume, circulatory shock or concurrent drugs that
reduce blood pressure. Monitor and warn patients about orthostatic hypotension.

Dependence/Tolerance
Physical dependence is common with chronic use. Do not abruptly discontinue chronic use; taper slowly. In patients
with chronic non-cancer pain, if the maximum recommended daily dose of 90 mg morphine equivalents is
exceeded, a reduction in dose is recommended with gradual tapering to the lowest effective dose. Methadone has
the same potential for physical and psychological dependence as other opioids. Partial agonist and agonist-
antagonist agents such as pentazocine can induce withdrawal in people who take opioids regularly.

With chronic use, patients develop tolerance to opioid-induced analgesia, nausea and sedation but not to opioid-
induced constipation. Patients established on methadone maintenance therapy for opioid dependence develop
tolerance to the analgesic, sedative and euphoric effects of methadone. The established maintenance dose of
methadone in these patients will consistently prevent withdrawal symptoms, but will not, by itself, meet their
analgesic requirements in the event of surgery or pain of another cause. If pain is not severe, non-opioid analgesics
such as NSAIDs can be used. For severe pain, pure opioid agonists may be used. The use of agonist-antagonists
should be avoided because of the possibility of precipitating withdrawal. See Action and Clinical Pharmacology,
Table 7 for a list of opioid agonists and agonist-antagonists. The use of opioid analgesics in patients on methadone
maintenance must be closely supervised at the lowest effective dose for the shortest period of time in conjunction
with nonpharmacological treatments and with appropriately frequent reassessment of their pain control needs.
Similar precautions are recommended for the use of drugs such as benzodiazepines or CNS stimulants in these
patients.

Endocrine and Metabolism

Rare but serious adrenal insufficiency has occurred. Use with caution in patients with Addison disease and monitor
for symptoms. Onset may range from 1 day to more than 1 year.

Severe hypoglycemia has occurred in patients taking tramadol. Hypoglycemia occurs early in therapy and has been
reported in both diabetic patients and nondiabetic patients, in both elderly and young patients, and at therapeutic
doses as well as in overdose. Risk factors may include diabetes, advanced age, renal impairment and overdose.

Caution in patients with hypothyroidism (increased risk of CNS and respiratory depression).

Gastrointestinal
Constipation occurs in the majority of patients with chronic use. It is essential to caution patients in this regard and
to institute an appropriate regimen of bowel management at the start of prolonged therapy. Bulk-forming laxatives
should be avoided. Nausea may be due to reduced bowel motility and may respond to prokinetic drugs.

Most opioids can induce spasm of the sphincter of Oddi, which can increase biliary tract pressure. Caution in
patients with biliary tract dysfunction.

Immune
It is important to determine the exact nature of the reaction in patients reporting allergy to opioids, as many patients
believe they are allergic after experiencing an exaggerated pharmacologic response to opioids such as nausea,
drowsiness or constipation. True allergic reactions are rare. In a patient with opioid allergy to one agent, it may be
possible to switch to an opioid of a different chemical structure. See Action and Clinical Pharmacology.

Neurologic
Central nervous system effects are common, dose-related and may be serious and of special concern in patients
taking other CNS depressant drugs concurrently. Patients should avoid alcohol while using opioids. See Drug
Interactions.

All opioids can increase CSF pressure; caution in patients with head injury or a history of seizures.

Serotonin syndrome is possible. See Drug Interactions.

Hyperalgesia that does not improve when the dose is increased has been reported with butorphanol, codeine,
fentanyl, meperidine, morphine, oxycodone, pentazocine, tapentadol and tramadol. Reduce dose or switch to a
different opioid.
Perioperative Considerations
See specific product monographs.

Psychiatric
Use with caution in patients with a history of addiction or suicidal tendencies. In the treatment of chronic non-cancer
pain, treat concurrent psychiatric problems such as anxiety and post-traumatic stress disorder to reduce the risk of
addiction and possibly reduce pain. Monitor patients during therapy for addiction, abuse and misuse.

Renal
Hyponatremia has occurred in patients taking tramadol. Although rare, serious cases of confusion, seizures and
hospitalization have been reported.

Respiratory
Respiratory depression and respiratory arrest are major toxicities associated with inappropriately high doses,
interactions with other CNS depressant drugs, impaired pulmonary function, accidental ingestion by children, and
use in the elderly and debilitated patients. Monitor patients especially when initiating therapy, switching between
opioids or increasing doses.

Rapid IV injection of opioid analgesics increases the incidence of adverse reactions such as severe respiratory
depression and apnea, as well as hypotension, peripheral circulatory collapse and cardiac arrest. The patient
should be lying down during IV administration. These drugs should not be administered intravenously unless an
opioid antagonist and the facilities for assisted or controlled respiration are immediately available.

Although agonist-antagonist opioids such as butorphanol, nalbuphine and pentazocine may demonstrate a “ceiling
effect” (above a certain high dose, respiratory depression does not increase with increasing doses), caution is
recommended especially in fragile patients such as children or the elderly and those taking other CNS depressants.

Sexual Function/Reproduction
Prolonged use can lead to reductions in sex hormones and amenorrhea, low libido and erectile dysfunction.

Special Populations

Pregnant Women

Therapeutic use of opioids during the 1​st trimester has been associated with congenital heart and neural tube
defects, but the risk appears to be small. Avoid use in the 1​st trimester if possible.

Avoid use in the 3​rd trimester if possible. Babies born to mothers who have been taking opioids regularly prior to
delivery will be physically dependent and display signs of neonatal abstinence syndrome: irritability, excessive
crying, tremor, hyperactive reflexes, diarrhea, sneezing, yawning, vomiting, abnormal sleep pattern, poor
feeding and, rarely, seizures if untreated. Monitoring is required at birth and over the first 2 weeks.

Certain opioid analgesics are approved for use to relieve pain during labour and delivery, e.g., nalbuphine and
epidural sufentanil. Neonatal respiratory depression, bradycardia and arrhythmias have occurred with
nalbuphine use during labour and delivery; use with caution and monitor the newborn. Other opioids are
contraindicated during labour and delivery due to the possibility of producing respiratory depression in the
neonate.

Many opioids are contraindicated in pregnancy by the manufacturer; refer to specific product monographs.

Methadone: Methadone is sometimes used during pregnancy in opioid-dependent women, even though the
fetus will be exposed to the drug and may experience withdrawal after delivery. Opioid dependence in the
mother is associated with premature delivery and low birth weight. The use of methadone in pregnancy is often
considered to be a safer and more manageable option than the possibility of continued illicit drug use, especially
if the mother is likely to engage in high-risk behaviours associated with procuring and using street drugs.
Methadone has been associated with increased risks of prematurity, low birth weight and ophthalmic
abnormalities. During pregnancy, there is an increase in its clearance and a shorter half-life; thus, dose
adjustment may be required.

Nursing Women
The use of opioids in lactation is controversial. Some authorities consider them generally compatible with
breastfeeding, while others recommend non-opioid analgesics when possible. Some agents are contraindicated
in lactation by the manufacturer; see specific product monographs. The amount of drug reaching nursing infants
is generally less than 10% of a maternal dose. Exposure to morphine and nalbuphine would be low due to poor
oral absorption in the infant. Since small amounts are present in breast milk, withdrawal symptoms can occur in
breastfeeding infants when maternal administration is stopped. Taper slowly. As well, sedation has been
reported in nursing infants exposed to opioids. If required, use low doses for a short duration and monitor
neonates for sedation and difficulty breathing.

Codeine: Health Canada and the US FDA advise against the use of codeine during breastfeeding unless the
benefits outweigh the risks [Health Canada. Important safety information on Tylenol with codeine in nursing
mothers and ultra-rapid metabolizers of codeine — for health professionals], [U.S. Food
and Drug Administration. FDA drug safety communication: FDA restricts use of prescription codeine pain and
cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women].
This recommendation is based on case reports of serious adverse events (including death) in infants exposed to
opioids from breast milk. It is suspected that breastfeeding mothers had an ultra-rapid metabolizer CYP2D6
genotype resulting in high morphine levels in maternal serum and consequently high morphine levels in breast
milk. A 2020 reanalysis of the data has called this into question [Clin Pharamcol Ther 2020;108(50;964-70]. Until
the controversy is resolved, codeine use in breastfeeding women should be limited to the lowest effective dose
for a maximum of 2–3 days. Breastfeeding mothers should be aware of the signs and symptoms of morphine
toxicity for themselves (constipation, oversedation) and their babies (drowsiness or sedation, difficulty
breastfeeding, breathing difficulties, and/or decreased muscular tone).

Tramadol: Tramadol is metabolized to a more potent active metabolite by CYP2D6; therefore, an increased risk
of toxicity may exist if the mother is a CYP2D6 ultra-rapid metabolizer. However, tramadol’s analgesic effect
involves other pathways (e.g., noradrenergic, serotonergic); fatalities associated with breast milk exposure have
not been reported.

Methadone: Women with opioid use disorders can continue methadone while breastfeeding. The amount of
drug present in breast milk may help to reduce withdrawal symptoms in infants born to opioid-dependent
mothers but is not usually sufficient to completely prevent withdrawal. However, cases of serious harm, including
death, have been reported in association with methadone exposure in breastfed infants [Health Canada.
Summary Safety Reviews Search. Methadone]. Infants breastfed by mothers on any maintenance opioid
therapy should be observed for increased sedation and respiratory depression; educate mothers on how to
identify these symptoms in their babies.

Pediatrics
Due to a lack of evidence that codeine, hydrocodone or normethadone are effective for treating cough and
because of potential risks in children and adolescents, products containing codeine, hydrocodone or
normethadone are not recommended for use in children and adolescents <18 years of age.
Not approved under 18 years of age: butorphanol, controlled-release codeine, fentanyl buccal/sublingual and
transdermal, hydromorphone, methadone, oral meperidine, oral morphine, nalbuphine, oral pentazocine,
remifentanil, tapentadol, tramadol.

Not approved under 12 years of age: immediate-release and injectable codeine, injectable morphine, injectable
pentazocine.

Geriatrics
There is an increased risk of respiratory depression due to possibly impaired renal and hepatic function. Elderly
patients may be more susceptible to fecal impaction if constipation occurs. Use low doses initially and monitor
carefully.

Meperidine and pentazocine are on the list of Beers Criteria for potentially inappropriate medication use in older
adults; they should be avoided. Opioids as a class should be avoided in older adults with a history of falls or
fractures, except for pain management due to recent fractures or joint replacement [CMAJ 2018;190(16):E500-
E506].

Monitoring and Laboratory Tests

Monitor respiratory and CNS function, especially when starting therapy and if increasing doses.

Occupational Hazards
Patients should be warned against driving or operating machinery if they become drowsy, dizzy or show impaired
mental and/or physical abilities.

Adverse Reactions

Adverse Drug Reaction Overview

The most common adverse reactions at therapeutic doses are constipation, dizziness, nausea and sedation. Life-
threatening and possibly fatal respiratory and CNS depression can occur. The incidence of most reactions,
including nausea and vomiting as well as CNS and respiratory depression, depends on dose and patient tolerance
of opioids.

More Common Adverse Drug Reactions (≥1%)

See Table 1.

Table 1: More Common Adverse Drug Reactions (≥1%)

Body System Effect Clinical Comment

Cardiovascular Prolongation of the QTc Dose-related. Very high doses may be associated
interval (methadone, with torsades de pointes.
buprenorphine).

Hypotension. Incidence depends on dose.

Body System Effect Clinical Comment

Central nervous “CNS excitation” with

system meperidine (attributed to its
metabolite normeperidine):
agitation, nervousness,
irritability, tremor, muscle
twitch, seizure.
“CNS stimulation” with
tramadol: anxiety, agitation,
confusion, nervousness,
euphoria, emotional lability,
hallucination (~10%).

Dizziness (common, up to May be due to postural hypotension. Lying down may

30%). help.

Headache (common, up to
16%).

Sedation (common, up to Tolerance usually develops.

43%).

Withdrawal syndrome: Can occur with abrupt discontinuation, or as a drug

tachycardia, chills, sweating, interaction between opioid agonists and antagonists.
restlessness, dilated pupils, Neonatal abstinence syndrome can occur if the
bone or joint aches, diarrhea, mother was taking chronic opioids close to delivery:
tremor, yawning, irritability, irritability, excessive crying, tremor, hyperactive
anxiety, runny nose. reflexes, diarrhea, sneezing, yawning, vomiting,
abnormal sleep pattern, poor feeding and, rarely,
seizures if untreated.

Dermatologic Hyperhidrosis (up to 16%).

Pruritus (4%).

Endocrine Hypoglycemia (with tramadol). Early onset.

Gastrointestinal Anorexia (up to 17%).

Constipation (common). Patients do not develop tolerance. Consider laxative

regimen.

Dry mouth (up to 20%).

Nausea (16–30%). Tolerance develops.

Vomiting (up to 16%).

Musculoskeletal Skeletal muscle rigidity Incidence depends on dose and IV infusion rate.
(common with fentanyl, Neuromuscular blocking drugs are given for
remifentanil, sufentanil) and prevention.
muscle movements (IV
fentanyl).
 Body System Effect Clinical Comment

Respiratory Cough (7–26% with fentanyl,

remifentanil, sufentanil).

Respiratory depression. Dose-related; may be fatal. See Drug Interactions.

Other Diversion for nonmedical use See Storage and Stability.

(5%).

Falls (up to 3%).

Opioid abuse disorder (5%).

Nonfatal overdose (0.1–1.8%). Increased risk with increased doses.

Less Common Adverse Drug Reactions (<1%)

Cardiovascular
Hypertension, tachycardia. Increased pulmonary artery pressure (butorphanol, pentazocine).

Dermatologic
Urticaria, Stevens Johnson syndrome, toxic epidermal necrolysis.

Endocrine and Metabolism

Adrenal insufficiency, increased prolactin, hyponatremia.

Gastrointestinal
Fecal impaction, biliary tract spasm.

Hepatic/Biliary/Pancreatic
Increased liver enzymes.

Immune
Anaphylaxis, rash.

Neurologic
Abnormal dreams, agitation, amnesia, anxiety, confusion, delirium, depersonalization, depression,
disorientation, dysphoria, euphoria, hallucinations, hyperalgesia, insomnia, nervousness, seizures, abnormal
thinking, tinnitus, tremor, twitching, vertigo.
Ophthalmologic
Miosis, visual disturbance.

Renal
Urinary retention, antidiuretic effect.

Respiratory
Respiratory arrest.

Sexual Function/Reproduction
Reduced sex hormones, amenorrhea, decreased libido, erectile dysfunction, infertility.

Drug Interactions

Serious Drug Interactions

CNS depressants: sedation, respiratory depression and death have occurred if taken with
opioids. Avoid alcohol. Avoid other CNS depressants (e.g., benzodiazepines, gabapentin,
pregabalin) if possible, or reduce doses and monitor.
MAO inhibitors (MAOIs): severe reactions, including respiratory depression, have occurred.
MAOIs are contraindicated within 14 days of opioids.
Drugs that prolong the QT interval may increase the risk of arrhythmias with buprenorphine and
methadone.
Serotonin syndrome is possible if opioids are combined with serotonergic drugs.
Do not coadminister carbamazepine and tramadol due to increased seizure risk and reduced
benefit.

Drug-Drug Interactions
Drug-drug interactions involving opioids are listed in Table 2.

Table 2: Drug-Drug Interactions

Interacting Drug Effect Clinical Comment

Alcohol Additive CNS depression, respiratory Avoid.

depression and death.

Anticholinergic drugs Additive risk of constipation or urinary Caution.

retention.

Benzodiazepines Additive CNS depression, respiratory Avoid if possible.

Interacting Drug Effect Clinical Comment
depression and death.

Cimetidine Increased levels of opioids metabolized by Caution, monitor.

CYP enzymes due to enzyme inhibition.

Ciprofloxacin Increased methadone levels, possibly by Caution.

inhibition of metabolism.

CNS depressants, e.g., Additive CNS depression, respiratory Avoid if possible.

antidepressants, sedating depression and death [Ann Intern Med
antihistamines, antipsychotics, 2018;169(10):732-4].
gabapentin, pregabalin, other
analgesics

Drugs that increase seizure risk, Additive risk of seizures. Caution.

e.g., some antidepressants

Didanosine Decreased bioavailability of methadone. Caution, monitor.

Drugs that inhibit CYP2D6, e.g., Decreased analgesic efficacy of opioids that Caution, monitor;
amiodarone, quinidine, some are metabolized by CYP2D6 to more potent depends on CYP2D6
antidepressants analgesics, e.g., codeine, hydrocodone, genotype of patient.
tramadol; increased levels and toxicity of the
parent opioid drug if metabolized by CYP2D6,
e.g., serotonin syndrome with tramadol.

Drugs that induce CYP3A4, e.g., Reduced levels of opioids metabolized by Caution, monitor.
phenobarbital, phenytoin, CYP3A4 (buprenorphine, fentanyl,
carbamazepine, rifampin methadone, oxycodone, sufentanil, tramadol).

Drugs that inhibit CYP3A4, e.g., Increased levels and toxicity of opioids Caution, monitor.
azoles, protease inhibitors, metabolized by CYP3A4 (buprenorphine,
macrolides, verapamil, diltiazem fentanyl, methadone, oxycodone, sufentanil,
tramadol).

Drugs that prolong the QTc Additive risk of QTc interval prolongation with Caution. Avoid with
interval or alter electrolytes, e.g., buprenorphine and methadone. buccal and
class I and III antiarrhythmics, transdermal
tricyclic antidepressants, buprenorphine.
calcium channel blockers,
diuretics

Monoamine oxidase inhibitors Severe adverse reactions. Contraindicated

within 14 days.

Non-nucleoside reverse Decreased methadone levels due to Caution, adjust dose.

transcriptase inhibitors, e.g., increased metabolism.
efavirenz, nevirapine, rilpivirine

Opioid agonist-antagonists or In patients who are opioid-dependent, acute Avoid if possible.

partial opioid agonists withdrawal can occur.

Serotonergic drugs, e.g., SSRIs, Increased risk of serotonin syndrome. Caution, monitor.
SNRIs, tricyclic antidepressants,
 Interacting Drug Effect Clinical Comment
triptans

Skeletal muscle relaxants Increased risk of respiratory depression. Caution.

Smoking Decreased levels of pentazocine due to Caution.

increased metabolism.

Warfarin Increased INR. Caution, monitor.

Mainly documented
for buprenorphine
and tramadol.

Drug-Food Interactions
Grapefruit juice inhibits CYP3A4 and may increase the effect of drugs metabolized by CYP3A4 such as methadone
and fentanyl. See Action and Clinical Pharmacology, Pharmacokinetics.

Drug-Herb Interactions
St. John’s wort as an inducer of CYP3A4 may increase the metabolism and reduce the effect of opioids
metabolized by CYP3A4 such as methadone and fentanyl. See Action and Clinical Pharmacology,
Pharmacokinetics.

Drug-Laboratory Test Interactions

Methadone may interfere with urine pregnancy testing.

Dosage and Administration

Dosing Considerations
Dosing and administration of all opioids should be individualized taking into account the following: the nature
and severity of pain and medical status of the patient (e.g., renal and hepatic function), daily dose, last use,
half-life and potency of other opioids or other medication given previously or concurrently, and the degree of
tolerance experienced. The use of potent opioid analgesics for the management of persistent pain should be
preceded by a thorough assessment of the patient and diagnosis of the pain and its cause.
Basic analgesic dosing information on fentanyl, morphine and methadone is provided in this monograph, as
well as dosing for indications that are not approved by Health Canada. Specific product monographs and
guidelines should be consulted for more detailed information. See Table 5 and Table 6 for approximate
analgesic equivalences.
For chronic non-cancer pain, initial doses should be less than 50 mg morphine equivalents daily. Maximum
doses should be less than 90 mg morphine equivalents daily. See Table 5 and the Canadian guideline for safe
and effective use of opioids for chronic non-cancer pain’s Opioid Manager. ISMP Canada has developed an
infographic intended to help prescribers, pharmacists, patients and their caregivers understand the concept of
morphine equivalence, the increased risk of harm at higher levels of morphine milligram equivalents per day
(MME/D), and where in the risk profile a specific opioid regimen sits.
 Switching opioids: for analgesia, refer to Table 5 and Table 6 for conversion ratios. Morphine equivalents are
used for conversion. To reduce the risk of overdose, convert to a lower dose of the new opioid. If the current
dose is high, give 50% or less of the new opioid converted to morphine equivalents. Otherwise, start with 60–
75% of the previous dose converted to morphine equivalents. For treatment of chronic non-cancer pain,
maximum doses should be less than 90 mg morphine equivalents daily, see Table 5. For conversion to
transdermal fentanyl, refer to the product monograph for a conversion table and guidelines. Use extreme
caution when switching from opioids to methadone due to a high risk of overdose even in patients who are
considered opioid tolerant.
Rapid IV administration can increase the risk of respiratory depression and hypotension.

Recommended Dose and Dosage Adjustment

Adults
See Table 3.

Table 3: Dose in Adult Patients

Dose Maximum Clinical
Indication Drug Route Initial Dose Titration Dose Comment

Breakthrough Fentanyl Buccal, 100 mcg is Use only 1 800 Not for use in
cancer pain sublingual the initial dose for mcg/dose. opioid-naive
in opioid- dose in all each Maximum 4 patients. Do not
tolerant patients episode of episodes of convert the dose
patients breakthrough breakthrough from a different
pain. If pain/day fentanyl
necessary, formulation or
increase the any other opioid
dose at the on a dosing
next episode equivalency
of basis; initial dose
breakthrough is always 100
pain. Do not mcg for the
repeat a buccal/sublingual
dose for at tablets.
least 2 h (4 h
for
effervescent
tablets)

IV Refer to
product
monograph

Transdermal Only used in

opioid-
tolerant
patients;
see product
monograph
for
conversion
from
previous
opioid dose
 Dose Maximum Clinical
Indication Drug Route Initial Dose Titration Dose Comment

Diabetic Tapentadol Oral 50 mg BID Increase 500 mg/day Individualize

neuropathy extended- dose at 3- initial dose.
(not a Health release day intervals
Canada– tablets
approved
use)

Dyspnea Morphine Oral Opioid- Various

(not a Health naive regimens are
Canada– patients: recommended.
approved 2.5–5 mg
use) may be
sufficient
In patients
receiving
opioids for
pain: mild
dyspnea:
25–50% of
usual
analgesic
dose;
moderate
dyspnea:
50–100% of
usual dose;
severe
dyspnea:
100% of
usual dose

Myocardial Morphine IV 2–4 mg Give Patients may

infarction every 5 min repeated require as
(not a Health small doses much as 25–
Canada– of 1–4 mg at 30 mg for
approved 5-min pain relief
use) intervals

Pain Methadone Oral 2.5–10 mg Increase In patients

(not a every 6–12 doses slowly stabilized on
Health h according to methadone,
Canada– patient additional
approved response. analgesics,
use) Full including opioids
analgesic at slightly higher
effect may than usual
not occur for doses, may be
3–5 days required to treat
acute pain.

Morphine Oral 10–30 mg Adjust dose 90 mg/day in

Q4H around to patient chronic non-
the clock response to cancer pain
Daily dose achieve the
should be lowest
 Dose Maximum Clinical
Indication Drug Route Initial Dose Titration Dose Comment
<50 mg in effective
chronic non- dose.
cancer pain Further
adjustments
are made at
3-day
intervals

IV, IM, SC 1–20 mg Adjust

Q4H according to
response

Rectal 10–20 mg Adjust

Q4H according to
response

Epidural Intermittent If required, 10 mg/day

epidural after 1 h,
injection: 5 additional
mg doses of 1–2
mg are given

Continuous If required, Up to 30
epidural additional mg/day may
infusion: doses of be required
2–4 mg/24 h 1–2 mg/day in some
are given patients

Intrathecal 0.2–1 Adjust Up to 20 Caution with

mg/day according to mg/day may doses above 20
response be required mg/day.
in some
patients

Opioid use Methadone Oral 15–30 mg Individualize Maintenance

disorder once daily to control dosage is
withdrawal usually in the
symptoms range of 50–
without 120 mg daily,
causing but may be
respiratory higher or
depression lower in
or excessive some
sedation patients

Geriatrics
Start with low doses and monitor.

Pediatrics
See Table 4.

Table 4: Dose in Pediatric Patients

 Initial Dose Maximum Clinical
Indication Drug Route Age/Weight Dose Titration Dose Comment

Pain Codeine Oral ≥12 y 15–30 mg 120 mg Contraindicated

Q6–8H as daily in the
needed postoperative
management of
pain in patients
≤18 y following
tonsillectomy
and/or
adenoidectomy.

Morphine IV Adolescents 3–5 mg Repeat in 5 10 Inject slowly

≥12 y Q4H min if mg/dose over at least 5
needed min.

Infants and 0.1–0.2 10

children <12 mg/kg mg/dose
y Q2–4H as
(not a needed
Health
Canada–
approved
use)

Neonates 0.05–0.2
(not a mg/kg
Health Q2–4H
Canada–
approved
use)

Oral, Adolescents 5–10 mg

rectal ≥12 y Q4H
(not a
Health
Canada–
approved
use)

1–11 y 0.2–0.3
(not a mg/kg
Health Q4H
Canada–
approved
use)

Neonates 0.05–0.2
1–11 mg/kg
months Q4H
(not a
Health
Canada–
approved
use)

SC Adolescents 2.5–10
 Initial Dose Maximum Clinical
Indication Drug Route Age/Weight Dose Titration Dose Comment
≥12 y mg Q4H

2–11 y 0.2 mg/kg

(not a Q4H
Health
Canada–
approved
use)

Neonates 0.1–0.2
up to 2 y mg/kg
(not a Q4H
Health
Canada–
approved
use)

Neonatal Morphine Oral Neonates 0.04 Reduce

abstinence mg/kg dosage
syndrome Q4H, frequency
(not a increasing gradually
Health the dose over
Canada– if 6–10 days.
approved necessary Discontinue
use) to control when a
symptoms dose of
0.04 mg/kg
once daily
is achieved

Renal Impairment
Reduce dose of buprenorphine/naloxone, butorphanol, codeine, fentanyl, hydromorphone, meperidine, methadone,
morphine, nalbuphine, oxycodone and tramadol. See product monographs. Some opioids are contraindicated in
severe renal impairment—see Contraindications.

Hepatic Impairment
Reduce dose of buprenorphine, buprenorphine/naloxone, butorphanol, codeine, fentanyl, hydromorphone,
meperidine, methadone, morphine, nalbuphine, oxycodone, pentazocine, tapentadol and tramadol. See Product
Monographs. Some opioids are contraindicated in severe hepatic impairment—see Contraindications.

Genetic Polymorphism
CYP2D6 is a polymorphic enzyme that converts codeine, hydrocodone and tramadol into metabolites with more
potent analgesic properties. In patients who are CYP2D6 ultra-rapid metabolizers, toxicity from codeine,
hydrocodone and tramadol is more likely to occur even at therapeutic doses. Patients with a CYP2D6 poor
metabolizer genotype or taking drugs that inhibit CYP2D6 will experience less analgesic effect. With tramadol, poor
CYP2D6 metabolizers are also at increased risk of serotonin syndrome due to enhanced inhibition of serotonin
reuptake by tramadol.

The incidence of the CYP2D6 ultra-rapid metabolizer genotype is 0.5–1% in Chinese, Japanese and Hispanics, 1–
10% in Caucasians, 3% in African-Americans, and 16–28% in North Africans, Ethiopians and Arabs. The CYP2D6
poor metabolizer genotype is found in 5–10% of Caucasians and 1% of Asians.

Table 5: Chronic Non-Cancer Pain—Oral Morphine Equivalents​[a]

 Initial Recommended Dose for Maximum Recommended Dose for
Treatment of Chronic Non-Cancer Treatment of Chronic Non-Cancer Pain:
Pain: <50 mg Morphine Equivalent <90 mg Morphine Equivalent Daily Dose​
Opioid Drug Daily Dose​[b] [b]

Codeine <334 mg/day <600 mg/day

Hydromorphone <10 mg/day <18 mg/day

Morphine <50 mg/day <90 mg/day

Oxycodone <33 mg/day <60 mg/day

Tapentadol <160 mg/day <300 mg/day

Tramadol <300 mg/day​[c] <540 mg/day​[c]

[a] Refer to Table 6 for analgesic equivalences when switching from one opioid to another.
[b] Conversion ratios may vary depending on individual variations and drug interactions.
[c] Maximum tramadol daily dose is 300–400 mg. Conversion ratio may be unreliable due to genetic polymorphisms and
drug interactions.

Table 6: Approximate Analgesic Equivalences​[a]

Approximate Equivalent Dose (mg; compared to morphine 10 mg IM)

Drug Parenteral Oral

Agonists

Codeine 120 200

Fentanyl​[b] 0.1 N/A​[b]

Hydromorphone 2 6

Meperidine (pethidine) 75 300

Morphine 10 Single or intermittent dosing: 60

Around-the-clock dosing: 30

Oxycodone N/A​[c] 15–20

Tapentadol N/A​[d] 100

Tramadol N/A​[d] 180​[e]

Agonist-Antagonists

Buprenorphine N/A​[f] N/A​[f]

 Approximate Equivalent Dose (mg; compared to morphine 10 mg IM)
Drug Parenteral Oral

Butorphanol 2 N/A​[c]

Nalbuphine 10 N/A​[c]

Pentazocine 60 180

[a] From single-dose studies using immediate-release dosage forms. These approximate analgesic equivalences should
be used only as a guide for estimating equivalent doses when switching from one opioid to another. Additional references
should be consulted to verify appropriate dosing of individual agents. See Dosage and Administration, Dosing
Considerations, Switching opioids for switching considerations.
[b] For initial dosing of fentanyl transdermal patches in patients currently receiving other opioids, consult specific dosing

conversion tables in the product monograph. For fentanyl buccal or sublingual, do not convert the dose from a different
fentanyl formulation or any other opioid on a dosing equivalency basis; initial dose for breakthrough cancer pain is always
100 mcg for the buccal/sublingual tablets. Consult the product monograph for full dosing and prescribing information.
[c] Route of administration not applicable.
[d] Analgesic potency relative to morphine is not established. Consult the product monograph for dosing recommendations.
[e] Maximum tramadol daily dose is 300–400 mg. Conversion ratio may be unreliable due to genetic polymorphisms and
drug interactions.
[f] Consult the product monograph for dosing and other prescribing information. Partial agonists such as buprenorphine
cannot substitute for full agonists since a withdrawal syndrome may occur. See also Indications and Clinical Use.
Abbreviations: N/A=not applicable.

Missed Dose
See the product monograph. For some opioids, such as buprenorphine and methadone, dose readjustment may be
required.

Administration
Doses of buprenorphine/naloxone and methadone are initially supervised by a health-care professional until the
patient is clinically stable and able to safely manage take-home doses. Avoid eating/drinking for approximately 30
minutes after administration of buccal buprenorphine.

In an effort to increase patient awareness of opioid-related risks, Health Canada has mandated that opioid warning
stickers and patient information handouts be provided with every opioid prescription at the point of sale, as of
October 2018 [Health Canada. Questions and answers: prescription opioids—sticker and handout requirements for
pharmacists and practitioners].

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre. See the
eCPS Directory section for a list of Poison Control Centres.

Signs and Symptoms

Respiratory depression (reduced respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis),
extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold or clammy skin, and sometimes
hypotension and bradycardia. Severe overdosage may result in apnea, circulatory collapse, cardiac arrest and
death. Miosis can be one characteristic of morphine derivative overdose. Mydriasis can take place in terminal
narcosis, severe hypoxia, or as a toxic effect of meperidine and oxycodone. Hyponatremia, hypoglycemia and
seizures, as well as typical opioid effects of CNS and respiratory depression, occur in tramadol overdoses.

Recommended Management
Call 911. Do not induce vomiting because of the risk of rapid onset of CNS depression. Establish adequate
respiratory exchange through the provision of a patent airway and institution of assisted or controlled ventilation.
There is controversy among provincial authorities as to whether or not chest compressions should be performed.
Naloxone, a pure opioid antagonist, is used as a specific antidote to reverse the effects of opioid agonists and
agonist-antagonists. An appropriate dose of naloxone should be administered, preferably by the IV route,
simultaneously with efforts at respiratory resuscitation. The usual initial adult dose of naloxone is 0.4–2 mg IV;
children: 0.01 mg/kg IV followed by 0.1 mg/kg if no response (see Naloxone (CPhA Monograph)). Naloxone is also
available as a single 2 mg and 4 mg/dose nasal spray (see Narcan Nasal Spray). Since the duration of action of the
opioid may exceed that of the antagonist, the patient should be under surveillance, and doses of the antagonist
should be repeated as needed to maintain adequate respiration. A neuromuscular blocking agent may be required if
respiratory depression is related to muscular rigidity. The possibility of precipitating withdrawal must also be
considered. Naloxone should not be used in the absence of clinically significant respiratory or cardiovascular
depression.

Buprenorphine binds tightly to opioid receptors; therefore, naloxone may not have a rapid and strong effect. The
relatively long duration of action of methadone compared to that of naloxone may necessitate repeated doses of
naloxone to counteract respiratory depression. A continuous IV infusion of naloxone may be used following the
initial bolus, at a rate of two-thirds the bolus dose per hour. Naloxone only partially reverses the symptoms of
tramadol overdose and can increase the risk of tramadol-associated seizures.

Action and Clinical Pharmacology

Mechanism of Action
Opioid analgesics act primarily on the CNS and the intestines. The perception of and emotional response to pain
are modified when opioid analgesics bind with stereospecific receptors in the CNS. The most studied subtypes of
opioid receptors are mu (μ), delta (δ) and kappa (κ). Pure opioid agonists such as morphine act primarily at the mu
receptor. Mixed agonist-antagonists such as butorphanol, nalbuphine and pentazocine are most active at the kappa
receptor. Buprenorphine is a partial agonist at the mu receptor and an antagonist at the kappa receptor. Methadone
is an opioid agonist that prevents withdrawal symptoms and reduces opioid cravings in individuals who are opioid-
dependent.

In addition to analgesia, opioid agonist activity in the CNS may cause suppression of the cough reflex, respiratory
depression, changes in mood such as euphoria or dysphoria, and EEG changes. Respiratory depression results
from direct action on brain stem respiratory centres. Opioids act directly on the cough centre in the medulla to
depress the cough reflex. Stimulation of the parasympathetic nucleus of the oculomotor nerve can produce miosis.
Nausea and vomiting result from stimulation of the chemoreceptor trigger zone as well as delayed gastric emptying.
Effects of opioids on the GI tract include decreased gastric, biliary and pancreatic secretions, as well as increased
rectal smooth muscle tone, and inhibition of peristalsis, which can lead to constipation. Oral products that combine
oxycodone with naloxone may reduce opioid-induced constipation: naloxone has poor oral bioavailability; therefore,
oral naloxone can block GI effects of opioids without blocking centrally mediated opioid analgesia. An effect on the
hypothalamic-pituitary-gonadal/adrenal axis can produce reduced sex hormones as well as adrenal insufficiency
with reduced cortisol production. Opioids can increase smooth muscle tone in the urinary tract, leading to dysuria or
urinary retention.

Opioids cause histamine release from mast cells in blood and tissues to varying degrees, resulting in vasodilation,
pruritus and hyperhidrosis. Peripheral vasodilation, reduced peripheral resistance and the inhibition of
baroreceptors can result in orthostatic hypotension and fainting. The propensity for an individual opioid to cause
anaphylactoid or anaphylactic reactions appears to be related (inversely) to its analgesic potency rather than to its
chemical structure. Meperidine has a higher propensity to cause histamine release than does fentanyl, for example.

Pure opioid agonists can be classified by structure:

Diphenylheptanes: methadone.

Phenanthrenes: codeine, morphine, hydrocodone, hydromorphone, oxycodone.

Phenylpiperidines: fentanyl, meperidine, remifentanil, sufentanil.

Tapentadol has a dual action as both an agonist at mu-opioid receptors and a norepinephrine-reuptake inhibitor.
Opioids activate the descending inhibitory pathways from the brain to the spinal cord, thereby reducing the
perception of painful stimuli. The release of norepinephrine in the spinal cord that occurs in this process is
enhanced by tapentadol.

Tramadol binds weakly to mu-opioid receptors and also inhibits the reuptake of norepinephrine and serotonin. It is
converted by CYP2D6 to O-desmethyltramadol (M1), a more potent agonist at mu-opioid receptors. Analgesia and
other opioid effects result from the combined actions of the parent drug and its M1 metabolite, while serotonergic
and other effects are attributed to the parent drug. Polymorphisms in CYP2D6 and drug interactions influence its
analgesic and toxic effects. See Dosage and Administration, Genetic Polymorphism and Drug Interactions.
Hyponatremia associated with tramadol may result from a dual action: stimulation of opioid receptors and increased
release of serotonin resulting in increased ADH secretion.

Pharmacokinetics
Absorption, distribution, metabolism and excretion: see Table 7 and product monographs for details.

Table 7: Pharmacokinetics
Cytochrome P450
Onset of Action Duration of Action Metabolism (where
Drug Route (minutes) (hours) applicable)

Agonists

Codeine Oral (immediate- 10–30 4–6 CYP2D6,​[a] CYP3A4

release)

IM, SC 10–30 4–6

Fentanyl Buccal/sublingual 15–30 4 CYP3A4

effervescent
tablets

Epidural 5–10 1–2

IM 7–15 1–2

IV Almost immediate 0.5–1

Sublingual (not 15–30 2

effervescent)
 Cytochrome P450
Onset of Action Duration of Action Metabolism (where
Drug Route (minutes) (hours) applicable)

Transdermal Continuously released to maintain

consistent serum concentration. Following
removal of a patch, fentanyl continues to
be absorbed from the skin

Hydrocodone Oral 10–20​[b] 4–6​[b] CYP2D6,​[c] CYP3A4

Hydromorphone Oral (immediate- 30 4–5 —

release)

Parenteral 15 4–5

Meperidine Oral 15 2–4 CYP2B6, CYP3A4,

(pethidine) CYP2C19​[d]
IM, SC 10–15 2–4

IV 1 2–4

Methadone Oral 30–60 24–48​[e] CYP3A4, CYP2B6,

CYP2C19 (less by
CYP1A2, CYP2D6
and CYP2C9)

Morphine Oral (immediate- 60 4–5 Morphine is mainly

release) metabolized by
glucuronidation
SC 50–90 4–5

IM 30–60 4–5

IV 20 4–5

Epidural 15–60 ≤24

Oxycodone Oral (immediate- 10–15 3–6 Mainly CYP3A4, also

release) CYP2D6

Remifentanil IV 1 5–10 min after —

discontinuation

Sufentanil IV 1 No data CYP3A4

Epidural 10 1–2

Tapentadol Oral (immediate- 75 to peak 4–6 CYP2C9, CYP2C19,

release) concentration CYP2D6
(secondary pathways​
[f]
)
 Cytochrome P450
Onset of Action Duration of Action Metabolism (where
Drug Route (minutes) (hours) applicable)
Tramadol Oral (immediate- 1 3–6 CYP2D6,​[g] CYP3A4,
release) CYP2B6

Agonist-Antagonists

Buprenorphine SL 30–60 24​[h] CYP3A4 (30% of a

dose)
Buccal Tmax: 2.5–3 hours Mean elimination
half-life: 27.6±11.2
h

Transdermal One dose: effective level reached in 12–

24 h, peak at 60 h. Continuously released
to maintain consistent serum
concentration (1 patch lasts 7 days)

Butorphanol Intranasal 30 3–4 —

Nalbuphine SC, IM 15 3–6 —

IV 2–3 3–6

Pentazocine Oral 15–30 ≥3 Possibly CYP1A2

IM, SC 15–20 2

IV 2–3 1

[a] Codeine is converted to morphine by CYP2D6. Patients with 2 or more copies of the variant CYP2D6*2 allele may
produce higher amounts of morphine and experience increased opioid effects. See Dosage and Administration, Genetic
Polymorphism.
[b] For hydrocodone, onset refers to the analgesic effect and duration refers to the antitussive effect.
[c] Hydrocodone is partly metabolized by CYP2D6 to hydromorphone.
[d] Meperidine is metabolized to a neurotoxic metabolite normeperidine with CNS stimulant properties.
[e] With repeated dosing.
[f] Polymorphisms not expected to significantly affect elimination; primarily conjugated with glucuronic acid.
[g] CYP2D6 converts tramadol to an active metabolite.
[h] When used daily for maintenance therapy in opioid dependence.

Special Populations

Gender

Oxycodone: Females have up to 25% higher plasma levels than males when adjusted for body weight.

Storage and Stability

 Store all opioids out of the reach of children and animals. Unused and expired products should be returned to a
pharmacy. For temporary storage, special sealed childproof containers can be obtained at a pharmacy. Store all
opioids in a secure place to avoid theft and misuse. Do not discard them in household trash or flush them down a toilet.
Used transdermal patches should be folded in half with the adhesive side adhering to itself and immediately stored
safely, then returned to a pharmacy.

Supplied
Please refer to Summary Product Information section.

CPhA Monographs are written by CPhA editors and are reviewed by expert physicians and pharmacists. CPhA recommends the full monograph be
used. Partial monographs should not be provided to patients or anyone else and are for use only by clients at their own risk. CPhA assumes no
responsibility for or liability in connection with the use of this monograph. Once printed, there is no guarantee the information is up-to-date. [Printed
on: 05-17-2024 04:50 PM]
CPS, Drug Information © Canadian Pharmacists Association, 2024. All rights reserved