Opioids

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Opioids are an analgesic, but have fell out of favour in the treatment of chronic pain in New Zealand. They currently only have a role in acute pain and chronic cancer related pain. Before the onset of tolerance, opioids exert their analgesic effects through peripheral, spinal, and supraspinal sites.

Definitions

Opiate: any compound that is structurally related to products found in opium. Opiates include the natural plant alkaloids such as morphine and codeine.

Opioid: any agent regardless of its structure that has the functional and pharmacological properties of an opiate.

Endogenous opioids: Naturally occurring ligands that act on opioid receptors.

Endorphin: Often used synonymously with endogenous opioid but also refers to the specific opioid β-Endorphin

Narcotic: Originally referred to any drug that induced narcosis or sleep, now associated with opioids often used in a legal context to refer to a variety of substances that have an abuse or addictive potential.

Classification

Chemical classification of opioids. Copyrighted

Classification by chemistry

There are four base molecules that give rise to four families of opioids

• Phenathrenes - prototypical opioids such as morphine, codeine, oxycodone
• Diphenylheptanes- methadone and propoxyphene
• Phenylpiperidines - pethidine, fentanyl, and other fentayl related compounds
• Benzomorphans - pentazocine only

Morphine structure in three dimensions

Morphine is the archetypal opioid and is the reference standard against for other opioids. It has a benzene ring with a phenolic hydroxyl group at position 3, as well as an alcohol hydroxyl groups at position 6 and at the nitrogen atom. Both of the position 3 and 6 hydroxyl groups can be converted to ethers or esters forming other compounds. The nitrogen group is in a tertiary form and this is important to its analgesic properties.

Tramadol doesn't fit into the above classes. It is an atypical opioid with partial mu agonist activity and central CABA, catecholamine, and serotonergic activities.

Classification by receptor affinity

• Opioid Agonists - Morphine, Codeine, Meperidine, Fentanyl, Sufentanil, Remifentanil, Methadone, Tramadol
• Opioid Agonist/Antagonists & Partial Agonists - Pentazocine, Nalbuphine, Butorphanol, Buprenorphine
• Opioid Antagonists - Nalorphine, Naloxone, Naltrexone, Naltrindole, Nalmefene

Classification by Exogenous Opioids Strength

According to the strength or potency based on the plasma concentrations at which they exert their effects. C₅₀ or the plasma concentration causing a 50% effect.

• Strong Opioids include fentanyl, sufentanil, and remifentanil
• Weak opioids include codeine and tramadol
• Intermediate group includes morphine, methadone, oxycodone, and buprenorphine

Classification by synthetic process

• Naturally occurring compounds - Morphine, Codeine, Thebaine, Papaverine
• Semi-synthetic compounds - Diamorphine (heroin), Dihydromorphone, Buprenorphine, Oxycodone
• Synthetic compounds - Pethidine, Fentanyl, Methadone, Alfentanil, Remifentanil, Tapentadol

Mechanism of Action

Endogenous Opioids

There are four known distinct families of endogenous opioid peptides, the most studied of which are the enkephalins, endorphins, and dynorphins. They function as neurotransmitters in the pleasure-reward and pain pathways, and may have a role with hormone secretion, thermoregulation, and cardiovascular control.

They all derive from their own large precursor protein. Enkephalins derive from Proenkephalin, endorphins derive from Pro-opiomelanocortin (POMC), and dynorphins derive from Prodynorphin. A fourth more recently discovered family are the endomorphins, but the precursor is unknown.

Opioid Receptors

There are three main types of opioid receptors: μ (MOP), δ (DOP), and κ (KOP). They belong to the rhodopsin family of GPCRs. The natural ligands interact with each receptor but don't do so exclusively. These are the endomorphins and β-Endorphin (μ), enkephalins (δ), and dynorphins (κ).

All receptors have analgesic effects, but most opioids with clinical relevance have primary agonist activity on μ (mu) receptors, and so are termed μ agonists. With increasing dose, analgesia theoretically occurs in a log linear fashion. While opioid agonists/antagonists and partial agonists have a ceiling effect.

Opioid receptors are found within the CNS as well as in peripheral tissues.

Effects of Opioid Receptors

	Mu (µ)	Delta (δ)	Kappa (κ)
	Mu1 - Supraspinal analgesia Mu2 - Sedation, vomiting, respiratory depression, pruritis, euphoria, stress coping, anorexia, urinary retention, physical dependence.	Spinal analgesia. Anxiolytic, positive affect	Spinal analgesia, sedation, dyspnoea, miosis, respiratory depression, dysphoria, negative affect, dependence
Endogenous Peptides
Enkephalins	++	+++
β-Endorphin	+++	+++
Dynorphin A	++		+++
Dynorphin B	+	+	+++
Endomorphin-1	+++
Agonists
Morphine	+++		+
Fentanyl	+++
Methadone	+++
Antagonists
Naloxone	−−−	−	−−
Naltrexone	−−−	−	−−−

Supraspinal Effects

Opioid receptors are highly localised in subcortical regions (thalamus, periaqueductal gray, rostral ventromedial medulla, and locus ceruleus). Descending pain-modulating pathways originate from these areas which are activated with opioids.

Opioids block the release of GABA from presynaptic inhibitory inter-neurons in these descending pain pathways. This leads to the activation of monoamine-containing descending neurons that supress nociceptive transmission in the dorsal horn. A reduction in GABA is also accompanied by release of dopamine leading to opioid addiction in some individuals.

Opioids can also antagonise NDMA receptors, thereby activating the descending serotonin and noradrenaline pain pathways. NMDA receptors are thought to be involved in neuropathic pain and the development of tolerance.

Spinal Effects

They are also found on presynaptic afferent fibres, interneurons, and postsynaptic projection neurons. In the spinal cord they are found in the dorsal horn, primarily in laminae I and II.

Presynaptically, opioids bind to presynaptic opioid receptors located on C and Aδ neuronal membranes, reducing cAMP signalling and suppressing the activity of voltage-gated calcium channels. They thereby prevent the release of endogenous pain neurotransmitters such as glutamate, substance P, and calcitonin gene-related peptide.

Postsynaptically, opioids activate inward potassium channels to cause hyperpolarisation of ascending projection neurons.

Specific Opioids

Morphine

• Low lipid solubility
• Slow onset action (slow BBB penetration)
• High 1st pass metabolism (LIVER)
• Metabolism CYP450 / glucuronidation
• 40-60% reach systemic circulation
• Renal excretion

Methadone

• Longer duration action
• Limited first pass metabolism
• High bioavailability
• ANTAGONIST NMDA receptor – Neuropathic pain
• Inhibits re-uptake NA/Serotonin
• Metabolised in Liver / excretes feaces (mostly)

Tramadol

• Phenylpiperidine analogue (Codeine)
• Modulation Serotonin and NA reuptake
• Less Respiratory depression
• Less GIT S/E (for comparable analgesic effect)

Tapentadol

• MOP receptor agonist
• NA reuptake inhibition
• Comparable opioid potency to Oxycodone

Ramifentanyl

• High Lipid solubility
• Rapid extra-hepatic metabolism

Codeine

• “Pro-drug”
• Converted to morphine for effect
• 5-10% population unable to convert / ineffective

Pethidine (Meperidine)

• Relative weak opioid (10% morphine)
• ++ anticholinergic effects
• Neurotoxic S/E (Particularly in renal disease)
  • Delerium
  • Excitation
  • Seizures

Opioid Potency Comparison

Opioid Potency and Half-life

Opioid Agonists	Potency	Half-life
Morphine	1	2 - 3.5
Hydromorphone	5 - 8	2 - 3
Oxycodone	1.5	2 - 3
Methadone	1	24
Fentanyl	100	3 - 4
Codeine	0.13	3
Tramadol	0.2
Sufentanil	1000
Alfentanil	20
Remifentanil	100

Conversion Ratios and Examples

Converting		Ratio	Example
from	to
Codeine oral	morphine oral	10:1	Codeine 60mg oral	-> morphine 6mg oral
Tramadol oral	morphine oral	10:1	Tramadol 100mg oral	-> morphine 10mg oral
Dihydrocodeine oral	Morphine oral	10:1	Dihydrocodeine 100mg oral	-> Morphine 10mg oral
Oxycodone oral	Morphine oral	1:1.5	Oxycodone 10mg oral	-> Morphine 15mg oral
Morphine oral	Oxycodone oral	2:1	Morphine 20mg oral	-> Oxycodone 10mg oral
Morphine oral	Morphine subcut	2 to 3:1	Morphine 30mg oral	-> Morphine 10-15mg subcut
Oxycodone oral	Oxycodone subcut	2:1	Oxycodone 20mg oral	-> Oxycodone 10mg subcut
Oxycodone subcut	Morphine subcut	1:1	Oxycodone 10mg subcut	-> Morphine 10mg subcut
Morphine oral	Fentanyl subcut	100:1	Morphine 30mg oral	-> Fentanyl 0.3mg subcut

Calculation of oral Morphine Equivalent Daily Dose (oMEDD)

oMEDD (mg) = Current Opioid Dose x Conversion factor

Renal Failure

Morphine in Renal Failure

	% Normal Dose	Dose (mg)	Dose Interval (hourly)
Mild renal impairment (GFR 20-50)	75%	2.5-5	6
Moderate renal impairment (10-20)	50%	2.5-5	6-8
Severe renal impairment (<10)	Use small doses	1.25-2.5	8-12

Tramadol in Renal Failure

	% Normal Dose	Dose (mg)	Dose Interval (hourly)
Mild renal impairment (GFR 20-50)	100%	50-100	6
Moderate renal impairment (10-20)	50%	50-100	6-8 (modify as needed)
Severe renal impairment (<10)	50%	50	6-8 (modify as needed)

Oxycodone in Renal Failure

	% Normal Dose	Dose (mg)	Dose Interval (hourly)
Mild renal impairment (GFR 20-50)	50%	2.5-5	6
Moderate renal impairment (10-20)	25-50%	2.5-5	6-8 (modify as needed)
Mild renal impairment (<10)	25-50%	2.5-5	8-12 (modify as needed

Fentanyl in Renal Failure

Fentanyl is metabolised in the liver to inactive metabolites. It is a useful Strong opioid in renal failure with stable pain. Fentanyl is available in patches.

Liver Failure

There is variable time of onset and analgesic efficacy. They are reasonably well tolerated in adjusted dosing. Ramifentanyl has no hepatic metabolism. Fentanyl patches are a good choice.

Variation in Sensitivity

Polymorphism in human OPRM1 gene which encodes the mu opoid receptor might contribute to variation in sensitivity.

Adverse Effects

See also: Opioid Deprescribing

Many of the long term effects come about from long term use. The evidence is clear that long term opioid use is not indicated in chronic non-malignant pain.

Long term use of opioids is associated with tolerance and opioid induced hyperalgesia. There is activation of pain facilitatory systems from the medulla that opposes the analgesic action, a "physiological antagonist of analgesia". With the activation of descending pain facilitatory pathways there can also be the induction of a paradoxical hyperalgesic state. This is termed opioid induced hyperalgesia. If unrecognised it can lead to ever increasing doses of opioids.

There are numerous other adverse effects such as neurohumoral effects which include hormonal dysregulation, immunosuppression, constipation, urinary retention, cardiovascular depression, motor system effects, respiratory depression, increased risk of falls, and impairment of sleep quality.