Page created on June 12, 2019. Last updated on January 7, 2022 at 22:28

Introduction to nociception

The main type of peripheral sensory neuron that mediates pain is the polymodal nociceptor (PMN). This is non-myelinated C-type fibre that responds to thermal, mechanical and chemical stimuli. The chemical stimuli that act on PMNs include bradykinin, protons and vanilloids like capsaicin, which is what makes spicy food spicy. The sensitivity of PMNs is increased by prostaglandins, which explains the hyperalgesia that occurs during inflammation.

The descending inhibitory pathway is a pathway from the brain that inhibits PMNs, thereby decreasing pain. This pathway goes through the periaqueductal grey area and the rostral ventromedial medulla in the medulla oblongata and ends in the substantia gelatinosa in the spinal cord.

Opioid analgesics in general

Introduction

Opioids are a class of drugs which bind to and activate opioid receptors. This makes them highly effective painkillers. The strongest painkillers available are opioids. Opiates are natural opioids, including morphine and codeine.

While they are highly effective painkillers and a very important cornerstone of modern medicine, they also have a very high potential for addiction and are easy to overdose on. Hundreds of thousands of people every year die from opioid-involved overdoses. Millions of people worldwide suffer from opioid addiction. This is partly the fault of the pharmaceutical companies which produce opioids, as they spent many years in the 1990s reassuring the medical community that they were not addictive (while likely knowing that they were). The situation has been termed the opioid crisis, which is something that I personally think everyone working in healthcare should know about.

Opioid receptors

Opioids bind to and activate opioid receptors. The endogenous ligands for these receptors are the so-called endorphins. Three opioid receptors are important. These are the μ, κ and δ opioid receptors (pronounced “mew”, kappa and delta, respectively). Of these three, the μ receptor is the most important for us as it causes the most analgesia, and it’s also responsible for some major unwanted effects, like respiratory depression, euphoria and dependence. Most clinically useful opioids are µ agonists with variable effect on the other opioid receptors.

All three opioid receptors are G_i-coupled receptors which open K⁺ channels in neurons. This causes hyperpolarization of the cells and inhibits release of other neurotransmitters.

Analgetic effects

Opioids (more specifically µ receptor agonists) cause analgesia by multiple mechanisms:

• The inhibit peripheral PMNs directly
• They inhibit the ascending pain pathways in the substantia gelatinosa
• They activate the descending inhibitory pathways
• They trigger release of endogenous opioids

Opioids are more effective on continuous dull pain than sharp pain. They’re even less effective on neuropathic pain. In addition to treating the pain itself, they also decrease the emotional impact of the pain.

Adverse effects

Opioids cause several adverse effects:

• Sedation (CNS depression)
• Respiratory depression
• Constipation
• Cough suppression (some opioids may be used as cough suppressants)
• Nausea
• Urinary retention
• Miosis
• Itching
• Euphoria (due to activation of the mesolimbic “reward” pathway)

Patients taking opioids chronically develop tolerance to most side effects, except two: constipation and miosis. These two side affects are not affected by tolerance, and so will remain despite chronic use of opioids. For this reason, chronic opioid use should be combined with high-fibre diet and laxatives.

Respiratory depression is the most dangerous side effect, and is the one which is responsible for death in case of overdose, as overdoses may cause breathing to cease completely.

Tolerance

Tolerance develops to some of the effects of opioids, but not to all. Pronounced tolerance develops to the analgesia, euphoria, respiratory depression and sedation, but no tolerance develops to the constipation and miosis.

Pharmacodynamic tolerance develops, where the expression of adenylyl cyclase is increased to counteract the G_i protein-mediated inhibition of the same enzyme.

Cross-tolerance refers to how building up a tolerance to one drug automatically builds up tolerance to another drug as well. Luckily there is very little cross-tolerance between different opioids, meaning that when tolerance has been developed to one opioid, switching to another opioid can return the analgesic effect (but also the side effects).

Opioid-induced hyperalgesia

Some patients who take opioids can develop increased sensitivity to pain. This is paradoxical, and the exact mechanism is unknown. It’s mostly seen in people who take opioids for a long time. Management should include decreasing the dose or weaning off the drug completely.

Contraindications

Pregnancy: Chronic opioid use in pregnant women causes the foetus to become dependant and experience withdrawal. However, short-term use of opioids is safe.

Biliary colic, renal colic: Opioids may worsen biliary or renal spasms.

Lung diseases (severe asthma, COPD), breathing problems: Due to respiratory depression.

Increased ICP: Opioids may worsen ICP due to pCO₂ elevation due to respiratory depression.

Drug interactions

Opioids should not be combined with drugs with sedative effects, like benzodiazepines, alcohol, or α₂ agonists due to the increased CNS and respiratory depression.

Combining opioids with MAO inhibitors or drugs that inhibit reuptake of monoamines like antidepressants or cocaine can cause serotonin syndrome.

Dependence, intoxication and withdrawal of opioids was described in topic 24.

Choice of opioid

• First choices for acute pain: Morphine or oxycodone
• First choices for chronic pain: Fentanyl (transdermal patch), oxycodone (extended-release formulation), methadone, etc.

Morphine

Both morphine and codeine are natural opioids, which are extracted from the opium poppy plant. Morphine is (together with oxycodone) usually the first-choice opioid to use as an analgesic. This is mostly based on reasons of familiarity, availability or cost rather than medical advantages.

Morphine is also the standard against which the analgesic efficacy of other opioids is compared, to calculate dose equivalents. For example, 15 mg of morphine is dose equivalent with approximately 10 mg of oxycodone, and 3,5 mg of hydroxymorphone.

Indications

Acute (trauma, burns, surgery) and chronic pain (especially cancer-related pain).

Mechanism of action

Strong µ opioid receptor agonist.

Dosing

Oral, subcutaneous, intravenous, intramuscular, epidural, spinal. Sustained-release oral preparations are often used for chronic pain. However, the bioavailability is variable and unpredictable, so other opioids are usually preferred for oral administration.

Morphine is dosed in the range of 2,5 – 15 mg when administered parenterally. When administered orally, 30 mg is approximately dose equivalent to 10 mg intravenously.

Pharmacokinetics

Morphine is biotransformed into an active metabolite in the liver. This active metabolite is excreted by the kidneys.

When administered i.m. or s.c., analgesic effect occurs after 15 – 30 minutes, and peaks at 45 – 90 minutes. When administered i.v., the analgesic effect occurs immediately and peaks at 20 minutes.

Contraindications

In kidney failure the active metabolite of morphine accumulates. Dosage should be reduced in this case.

Interactions

General interactions for opioids.

Side effects

General interactions for opioids.

Codeine

Codeine is (as with morphine) a natural opioid (an opiate), also extracted from the opium poppy plant. It’s not frequently used as a painkiller due to its unfavourable and unpredictable pharmacokinetics.

Indications

As a cough suppressant in case of severe dry cough. May be used for mild pain, but rarely.

Mechanism of action

Codeine itself is a weak-moderate µ opioid receptor agonist. Most of its effects come from its metabolite, morphine.

Dosing

Oral.

Pharmacokinetics

Codeine is a prodrug that is metabolised into morphine in the liver by CYP2D6.

Genetic differences can significantly influence how much of the codeine is metabolised into morphine and therefore the clinical effect of codeine. In most people only 10% of administered codeine is metabolised into morphine. However, some people have high CYP2D6 activity, causing codeine to have similar effects as morphine. Some people have low CYP2D6 activity, causing codeine to have very little effect. As such, the clinical effect of codeine is unpredictable.

Contraindications

In kidney failure the active metabolite of morphine accumulates. Dosage should be reduced in this case.

Side effects

Constipation. Other side effects of opioids are not common.