Morphine receptors are found centrally within the human brain, but also within the terminal axons of primary afferent neurones in lamina 1 & 2 (substantia gelatinosa) of the spinal cord.

The opioids have two well-established direct G protein-coupled actions on neurons: (1) they close voltage-gated Ca2+channels on presynaptic nerve terminals and thereby reduce transmitter release, and (2) they hyperpolarize and thus inhibit postsynaptic neurons by opening K+ channels.

All three major receptors are present in high concentrations in the dorsal horn of the spinal cord. Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them (Figure 31–2, sites A and B). Although opioid agonists directly inhibit the dorsal horn pain transmission neurons, they also inhibit the release of excitatorytransmitters from the primary afferents.

Mechanisms of side effects

a. Analgesia—Pain consists of both sensory and affective (emo-tional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience, especially the affective aspect. In contrast, nonsteroidal anti-inflammatory analgesic drugs have no significant effect on the emotional aspects of pain.

b. Euphoria—Typically, patients or intravenous drug users whoreceive intravenous morphine experience a pleasant floating sensa-tion with lessened anxiety and distress. However, dysphoria, an unpleasant state characterized by restlessness and malaise, may sometimes occur.

c. Sedation—Drowsiness and clouding of mentation are com-mon effects of opioids. There is little or no amnesia. Sleep isinduced by opioids more frequently in the elderly than in young, healthy individuals. Ordinarily, the patient can be easily aroused from this sleep. However, the combination of morphine with other central depressant drugs such as the sedative-hypnotics may result in very deep sleep. Marked sedation occurs more frequently with compounds closely related to the phenanthrene derivatives and less frequently with the synthetic agents such as meperidine and fentanyl. In standard analgesic doses, morphine (a phenan-threne) disrupts normal rapid eye movement (REM) and non-REM sleep patterns. This disrupting effect is probably characteristic of all opioids. In contrast to humans, a number of species (cats, horses, cows, pigs) may manifest excitation rather than sedation when given opioids. These paradoxic effects are at least partially dose-dependent.

d. Respiratory depression—All of the opioid analgesics canproduce significant respiratory depression by inhibiting brain-stem respiratory mechanisms. Alveolar PCO2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide challenge. The respiratory depres-sion is dose-related and is influenced significantly by the degree of sensory input occurring at the time. For example, it is possible to partially overcome opioid-induced respiratory depression by stimulation of various sorts. When strongly painful stimuli that have prevented the depressant action of a large dose of an opioid are relieved, respiratory depression may suddenly become marked.

A small to moderate decrease in respiratory function, as measured by PaCO2 elevation, may be well tolerated in the patient without prior respiratory impairment. However, in individuals with increased intracranial pressure, asthma, chronic obstructive pul-monary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Research is ongoing to understand and develop analgesic agents and adjuncts that avoid this effect. Research to overcome this problem is focused on μ-receptor phar-macology and serotonin signaling pathways in the brainstem respiratory control centers.

e. Cough suppression—Suppression of the cough reflex is awell-recognized action of opioids. Codeine in particular has been used to advantage in persons suffering from pathologic cough and in patients in whom it is necessary to maintain ventilation via an endotracheal tube. However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruc-tion and atelectasis.

f. Miosis—Constriction of the pupils is seen with virtually allopioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops (Table 31–3); thus, it is valuable in the diagnosis of opioid overdose. Even in highly tolerant addicts, mio-sis is seen. This action, which can be blocked by opioid antago-nists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine.

g. Truncal rigidity—An intensification of tone in the largetrunk muscles has been noted with a number of opioids. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but there is now evidence that it results from an action at supraspinal levels. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly adminis-tered intravenously. Truncal rigidity may be overcome by admin-istration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents.

h. Nausea and vomiting— The opioid analgesics can activatethe brainstem chemoreceptor trigger zone to produce nausea and vomiting. There may also be a vestibular component in this effect because ambulation seems to increase the incidence of nausea and vomiting.

I.Temperature—Homeostatic regulation of body temperatureis mediated in part by the action of endogenous opioid peptides in

the brain. This has been supported by experiments demonstrating that administration of μ-opioid receptor agonists such as morphine administered to the anterior hypothalamus produces hyperthermia, whereas administration of κ agonists induces hypothermia.

2. Peripheral effects

a. Cardiovascular system—Most opioids have no significantdirect effects on the heart and, other than bradycardia, no major effects on cardiac rhythm. Meperidine is an exception to this gener-alization because its antimuscarinic action can result in tachycardia. Blood pressure is usually well maintained in subjects receiving opi-oids unless the cardiovascular system is stressed, in which case hypotension may occur. This hypotensive effect is probably due to peripheral arterial and venous dilation, which has been attributed to a number of mechanisms including central depression of vasomotor-stabilizing mechanisms and release of histamine. No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected. However, caution should be exercised in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension. Opioid analgesics affect cerebral circulation minimally except when PCO2 rises as a consequence of respiratory depression. Increased PCO2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.

b. Gastrointestinal tract—Constipation has long been recog-nized as an effect of opioids, an effect that does not diminish with continued use. That is, tolerance does not develop to opioid-induced constipation (Table 31–3). Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system as well as the CNS. In the stomach, motil-ity (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase—particularly in the central portion; gastric secretion of hydrochloric acid is decreased. Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive contractions is markedly decreased. In the large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel actions are the basis for the use of opioids in the management of diarrhea, and constipation is a major problem in the use of opioids for control of severe cancer pain.

c. Biliary tract—The opioids contract biliary smooth muscle,which can result in biliary colic. The sphincter of Oddi may con-strict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels.

d. Renal—Renal function is depressed by opioids. It is believedthat in humans this is chiefly due to decreased renal plasma flow. In addition, μ opioids have been found to have an antidiuretic effect in humans. Mechanisms may involve both the CNS and peripheral sites. Opioids also enhance renal tubular sodium reab-sorption. The role of opioid-induced changes in antidiuretic hor-mone (ADH) release is controversial. Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, espe-cially in postoperative patients. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone.

e. Uterus—The opioid analgesics may prolong labor. Themechanism for this action is unclear, but both peripheral and central actions of the opioids can reduce uterine tone.

f. Neuroendocrine— Opioid analgesics stimulate the release ofADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone. These effects suggest that endogenous opi-oid peptides, through effects in the hypothalamus, regulate these systems (Table 31–1).

g. Pruritus—Therapeutic doses of the opioid analgesics produceflushing and warming of the skin accompanied sometimes by sweating and itching; CNS effects and peripheral histamine release may be responsible for these reactions. Opioid-induced pruritus and occasionally urticaria appear more frequently when opioid analgesics are administered parenterally. In addition, when opioids such as morphine are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso.

h. Miscellaneous— The opioids modulate the immune systemby effects on lymphocyte proliferation, antibody production, and chemotaxis. In addition, leucocytes migrate to the site of tissue injury and release opioid peptides, which in turn help counter inflammatory pain. However, natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids. Although the mechanisms involved are com-plex, activation of central opioid receptors could mediate a sig-nificant component of the changes observed in peripheral immune function. In general, these effects are mediated by the sympathetic nervous system in the case of acute administration and by the hypothalamic-pituitary-adrenal system in the case of prolonged administration of opioids.

Details of specific opioids

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Morphine

- Definitely avoid in renal impaired patients - Active metabolite M6G can get to toxic levels

- Less active metabolite M3G likely gives neurotoxic side effects (myoclonus, allodynia, hyperalgesia)

- Metabolites require renal excretion

- Likely the most immunosuppressive opioid

Hydromorphone

- Hydromorphone has less adverse effects of sedation, nausea and vomiting than morphine

- Hydromorphone is more lipid-soluble than morphine --> bioavailability is increased

- Hydromorphone is metabolised to hydromorphone-3-glucoronide in lower levels than morphine-3-G

- This metabolite can accumulate in renal failure - so NOT to be used

- Quicker onset and strong opioid possibly leads to greater harm/addiction potential

Oxycodone

- Oxycodone also has a better side effect profile than morphine

- Faster onset of action - so more useful in perioperative settings

- Sedation and itch are less with oxycodone than with morphine

- Metabolised by CP450 hepatic - to oxymorphone and noroxycodone (a weaker mu agonist)

- Metabolism can vary quite a bit between patients - so some have higher metabolites and possibly higher toxicity

- Higher risk of abuse than morphine

- NB: St Johns wort SIGNIFICANTLY reduces the effects of oxycodone! (includes metabolism)

Fentanyl

- Fentanyl does not require an active GI tract (can be given buccal, transdermal etc) so useful in dysphagia or GI problems

- Fentanyl also goes through liver - C P450 system

- Takes 3 days to reach steady state - so slower to adjust

- Very useful in renal failure

Tramadol

- Tramadol is a mu receptor agonist AND SNRI - so good for neuropathic pain and fibromyalgia

- Weak opioid agonist

- Metabolised by CYP2D6 to active metabolite M1. This is more potent than parent drug

- SO poor metabolises receive less analgesia effect

- Metabolised by the liver and increased risk of seizures and serotonin syndrome

- Seizure risk increases at higher levels

- Less risk of addiction than other opioids

- N&V is similar to morphine but less GI motor problems

- Less respiratory suppression than equiv morphine doses

- Withdrawal begins 12-20 hours after last dose (4)

- Withdrawal tends to last longer than other opioids (4)

Methadone

- It is cheap

- Rapid onset after taking orally

- Opioid receptor agonist and SNRI but variable exposure and half-life

- Has some effects also at NMDA receptor

- Can prolong the QTc interval - so monitor these issues

- Very unpredictable half-life leading to accumulation difficulties

- Metabolism is via CP450 - so interactions with other drugs can cause significant issues

(Fundamentals of Pain medicine, 2018)

Codeine

- Caution in breast feeding women (rapid conversion of codeine to morphine can lead to toxicity)

- Lower risk of overdose than other opioids

- When switching from codeine to another - beware they may have NO opioid tolerance

- 200 times weaker affinity for mu receptor

- 10% covered to morphine via CYP2D6

- Most common prescription associated opioid fatal overdoses in Victoria!

Buprenorphine

- There is a ceiling effect for respiratory depression but not for analgesia

- Withdrawal symptoms may occur if buprenorphine is ceased after long-term treatment; but symptoms are milder and more delayed in onset (≥72 hours)

- Buprenorphine binds strongly to the mu receptor site, but does not fully activate it. So if you give another opioid to someone on buprenorphine - it may not be as effective

Tapentadol

- Weak mu agonist and noradrenaline reuptake inhibitor (helping descending pathway modulation)

- Has no active metabolites

- Reduced GI side effects cw morphine

- Does NOT affect heart rate or blood pressure due to its noradrenaline reuptake inhibitor factors

- Liver metabolised - so not a good choice in chronic liver disease

Relative strengths:

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(NB Caveat: This has been written by me from references. Please check your own references before using these details for patient care. I take no responsibility for the information provided and this is for indicative/informative purposes only)

Reference for Methadone: AAFP Chronic pain management toolkit

https://www.aafp.org/dam/AAFP/documents/patient_care/pain_management/conversion-table.pdf

Tapering opioids / Rotation:

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https://www.nps.org.au/assets/NPS-MedicineWise-opioid-tapering-algorithm.pdf

Starting a buprenorphine patch:

NB: The importance of coming down to 30 mg oral morph equiv before starting the patch - otherwise they may experience withdrawal symptoms due to ceiling effect of But

- When ceasing patches, doses should be weaned down every 7 days to avoid withdrawal symptoms

- No tapering needed in renal impairment

- Contraindicated in severe hepatic impairment and risk in the elderly

Rotation NOTE this is in palliative care...

Reference: eTG 2020

Opioid use in certain groups:

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Pregnancy and breastfeeding:

- Avoid at all costs

- Lower all doses to lowest possible dose

- Highest risk time is first trimester and just before birth

- Breastfeeding opioids are ok EXCEPT codeine

Opioids and driving (reference 2):

- Opioids affect driving through: sedation; diminished reaction times, reflexes and coordination; reduced peripheral vision due to the persistent miotic effects and decreased ability to concentrate

- No direct clear evidence of link between driving accidents and opioids OTHER THAN first week when starting therapy and when increasing doses

- No opioid is clearly better than any other

- Sustained long-acting doses does not have evidence for affecting driving

- People cannot have an unconditional licence if they have a substance use disorder or alcohol disorder

- Can have a conditional licence if they are in a treatment program and been in remission for 3 mths, absence of cognitive or organ impairment

- If in doubt, they must have an OT driving assessment

- Miosis may cause problems with driving at night

Opioids and OSA:

- Avoid opioids in patients with moderate to severe OSA. And do not prescribe if they are severe and untreated at all

Opioids in over 65 yo:

- Consider falls and cognitive effects significantly

- Mitigate risks of constipation

- Start lower, go slower, frequent monitoring, taper benzos

- Older patients are more sensitive to opioids so dose approx 50% or less

Renal disease:

- Avoid morphine, diamorphine and codeine (and tapentadol if < 30 ml/min)

- Reduce Hydromorphone, methadone, morphine, and tramadol

- Can use buprenorphine, fentanyl and paracetamol. Oxycodone is ok.

- Dialysis - Hydromorphone is choice

Liver disease:

- Remember - hard to 'grade' liver impairment

- Opioids can worsen sedation, constipation, and encephalopathy. Hypoalbuminaemia will make drug availability higher. Use IR and not CR versions.

- Tramadol or oxycodone if lower pain, fentanyl and buprenorphine are relatively safe

Notification requirements:

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Urine drug screens

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- Consider at the first prescription

Opioid related mental health disorders

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Dependence

Rotation of opioids

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Opioid withdrawal symptoms

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Abstinence

- If someone goes complete abstinence...

- Onset, intensity and duration depend on the half-life of the abused drug

- Morphine and heroin = 6-10 hrs - peak 36-48hrs, then subside and gone by 5 days

- Methadone = < 30 hrs - peak several days - can last 2 weeks. Symptoms less severe

Symptoms of withdrawal are uncomfortable, but not life threatening

NB: The expression 'kicking the habit' likely comes from muscle spasms causing leg movements in opioid withdrawal

Detoxification commonly done with methadone or buprenorphine as withdrawal symptoms are less severe

Clonidine commonly used to help symptoms by reducing: anxiety, agitation, muscle aches, sweating, rhinorrhea, and muscle cramping. Side effects include: bradycardia, hypotension, dry mouth and drowsiness. Patches are 'smoother' than oral

Can also use: promethazine for N&V, loperamide for diarrhoea, ibuprofen for pain

Opioid metabolism

Tolerance (4)

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Tolerance develops to analgesic, euphoric, and mental clouding, sedation, respiratory depression, antidiuresis, N&V, and cough suppressive effects

Moderate tolerance occurs to bradycardia

Minimal tolerance to miosis, constipation, and seizures

Opioid induced hyperalgesia (OIH) is a type of tolerance.

Drug interactions with opioids to know (4)

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Synergistic effects with antipsychotic agents to depress cognition and respiration. Hyperpyrexia, hypertension and coma have been reported with MAOIs

Erythromycin increases the effects of opioids

Rifampicin decreases the effects of opioids

Carbamazepine, phenytoin, and barbiturates (anti seizure medications) enhance metabolism of opiates that use hepatic metabolism (e.g. fentanyl)

Benzodiazepines

TCAs

Metoclopramide

Long term effects of opioids

Questions to ask to inquire about readiness to change:

What do you know about the long-term use of opioids?
What do you think are the upsides and downsides of continuing to take opioids?
How do you see yourself in a few weeks or months’ time if you were able to reduce or stop the opioids?
What worries you about reducing your opioid dose?
What do you want to be able to do day-to-day that you can’t do right now?

Analgesia: How do you rate the pain? How much relief are opioids providing?
Activity: Are you achieving your functional goals?
Adverse effects: Are you experiencing any harms or side-effects from opioids such as constipation, drowsiness, sexual dysfunction or falls?
Affect: Have you been experiencing any mood changes eg, depression or low mood?
Aberrant behaviour: Have you been taking the opioids as prescribed? Have you increased your dose lately or have you used opioids to treat other symptoms eg. anxiety?

Quiz GENERAL opioid information:

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References:

1. Canadian guidelines for safe and effective use of opioids

https://nationalpaincentre.mcmaster.ca/opioid/cgop_b02_r08.html

2. Ackermann, E., Litt, J., & Morgan, M. (2017). Prescribing drugs of dependence in general practice, Part C1: The role of opioids in pain management.

https://www.racgp.org.au/download/Documents/Guidelines/Addictive-drugs/Addictive-drugs-guide-C1.pdf

3. Padma Gulur, Katharine Koury, Paul Arnstein, Hang Lee, Patricia McCarthy, Christopher Coley, Elizabeth Mort,"Morphine versus Hydromorphone: Does Choice of Opioid Influence Outcomes?",Pain Research and Treatment,vol. 2015,Article ID 482081,6pages,2015.https://doi.org/10.1155/2015/482081

4. Milhorn H.T. (2018) Opioid Dependence. In: Substance Use Disorders. Springer, Cham. https://doi-org.ezproxy.anzca.edu.au/10.1007/978-3-319-63040-3_6

5. Pregnancy and analgesia https://www.nps.org.au/assets/f4cd8a064d47b62a-0e01df33044e-139fddfcb7c79fd0c38a7065fad62081b237334047fed3a63e4463e31f34.pdf

6. opioid safety in pregnancy

https://eurekalert.org/pub_releases/2021-02/b-nlb020821.php

Opioid Wisely!

2. Peripheral effects

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