Opioid Analgesics Flashcards
What are the 3 opioids given at each step of the WHO three-step analgesic ladder
- Non-Opioids e.g e.g. Paracetamol or NSAIDs (Aspirin)
- Weak- Opioids e.g. Codeine, Tramadol
- Strong Opioids e.g. Morphine, Fentanyl
What is the pain relief ladder associated with ?
Cancer pain
What is given with opioids to help manage pain
Given an Adjuvant which is not typically used for pain, but helps with the management e.g. antidepressants (Amitriptyline), anticonvulsants (Gabapentin, Carbamazepine)
History of Opioids:
- Where does the word opium stem from ?
- How many alkaloids does opium contain?
Greek for juice of the poppy
- Contains 20 distinct alkaloids
- Who extracted morphine from poppy plant and in which year?
Friedrich Serturner in 1806
in which year did the proposal that opioids produce analgesia through receptor interaction occur ?
1950s
When was synthetic morphine developed and why
1921 - synthetic morphine (hydromorphine) developed – more potent less neurotoxic effects - Narcotics (opiates, opioids and derivatives)
Who and when was it discovered that endogenous opiates active opioid receptors
1975 and by Hughes & Kosterlitz they proposed and discovered that endogenous opiates activate opioid receptors (enkephalins (brain), endorphins, dynorphins
Define Opioids and Opiates and highlight the differences between them
Opioid: any substance (endogenous or synthetic) that produces morphine-like effects, blocked by antagonists (naloxone)
Opiate: compounds such as morphine and codeine (only endogenous) that are found in the opium poppy
- Opiates are only endogenous but opioids can be synthetic
Define an Analgesic drug
Define a Narcotic analgesic
Analgesic: a drug or agent which relieves and prevents pain without causing loss of consciousness
Narcotic analgesics: old term for opioids (induce sleep), hijacked as a generic term for drugs of abuse
Rank the analgesic effect of morphine, codeine and diamorphine (heroin)
- Diamorphine /diacetylmorphine
- Morphine
- Codeine
- The potency increases with the increase of the diacetyl groups
Therapeutic uses of Opioids:
What are the 4 main therapeutic categories/effects of opioids?
Provide details for each therapeutic category /effect
- Analgesia (Pain) – acute and chronic
Limbic System: Euphoria effect
Cortex/Midbrain: Antinociceptive
Alters perception to pain - Dyspnoea (Breathlessness)
Medulla: reduced sensitivity to hypoxia
Treat shortness of breath associated with Acute pulmonary oedema and myocardial infarctions - Depression of Cough Reflex
Brainstem cough centre at the receptor level - Antitussive effect (stops coughing ) - Diarrhoea Stomach/Intestines: increase tone, reduce motility and delay the transit time so we can get –>
Associated with increased water and electrolyte reabsorption
Unwanted effects of Opioids:
What are the 5 unwanted effects of opioids?
Provide details for each effect
Overstimulation can cause the following:
1. Respiratory Depression
Brainstem: reduced sensitivity of respiratory centre to arterial carbon dioxide
- Constipation:
GI tract myenteric plexus: reduce gastric emptying, increase tone, reduce motility - Nausea & Vomiting
Medulla Chemoreceptor Trigger Zone - Pruritus (Itching)
Mast cell: histamine release leading to Urticaria (hives) - Bronchoconstriction
due to Mast cells releasing histamine
Contraindication: asthmatic patients - Pupil constriction
Oculomotor Nucleus: stimulation
Observed in opioid-dependent drug users
Descending pain control system:
Where along the nociceptive pathway do opioids have an effect
Opioids have an effect at the dorsal horn of the spine -> where excitation of transmission neurons occurs -> b4 transmission continues to travel to the brain.
How do opioids have an effect along the nociceptive pathway?
Bind to receptors on the Descending pain pathway from the midbrain and brainstem and have an inhibitory effect.
Where are the opioid receptors found? and give the specific names
These receptors can be found in the
The cortex of the brain: A: amygdala, IC: insular cortex and H: hypothalamus
Midbrain : PAG: periaqueductal grey
Medulla of the brain: RVM: rostroventral medulla
Spinal cord: DH: dorsal horn
What are the 3 ways opioids cause analgesia?
BY :
- Activating the descending pathways
- Inhibiting transmission in the dorsal horn
- Inhibiting excitation of sensory nerve terminals in the periphery
What are the 2 opioid MoA?
- Pre-Synaptically :
Opioids bind to the opioid receptors –>
Inhibiting Ca2+ channels from opening - so there’s no influx of ca2+ so no neurotransmitters are released –>
Reduction in NT release into the synaptic cleft
BUT Excitation is possible through the inhibition of inhibitory neurones - Post - Synaptically
Opioids bind to the opioid receptors –>
Open K+ channels
Facilitate hyperpolarising as K+efflux across the plasma membrane
Limiting neuronal excitability
What regulates the opioid euphoric feeling
the Limbic system
What regulates the opioid Antinociceptive (pain relief) effect ?
the Cortex/Midbrain
What regulates the opioid Antinociceptive (pain relief) effect?
the Cortex/Midbrain
What are the 5 route of opioid administration?
- Oral: and be sublingual
- Injection: intravenous, intramuscular, subcutaneous
- Transdermal patch: epidermal
- Intrathecal opioid infusion: administered via an implantable infusion pump in the spinal cord- (long-term chronic pain)
- Patient-controlled analgesia (PCA): a pump that allows you to take control of your pain relief
what are 2 common examples of Opiate analgesics?
Morphine and Codeine - found naturally in poppies
What are the Main Pharmacological effects of morphine?
Morphine (1806)
Main pharmacological effects: analgesia, euphoria, sedation, respiratory depression, suppression of cough, pupillary constriction, reduced GI motility (constipation), histamine release (itching, bronchoconstriction, hypotension)
What are the main Unwanted side effects of Morphine ?
What are the effects with an acute overdose of morphine
Most troublesome unwanted effect :
- nausea & vomiting
- reduced GI motility (constipation)
- respiratory depression,
- addiction
Acute overdose: coma and respiratory depression
Codeine is a weaker opiate analgesic than morphine. How much weaker?
Codeine Has 20% analgesic potency of morphine
Codeine is a weaker opiate analgesic compared to Morphine.
How much weaker ?
and why
Codeine has 20% analgesic potency of morphine
Due to a methyl group added
What are the therapeutic uses of Codeine?
Therapeutic use:
mild-to-moderate pain (headache),
diarrhoea,
a cough suppressant (dose; antitussive< analgesic)
What is codeine usually combined with ? and what does it produce
Analgesic preparations: combine codeine (8 mg) with paracetamol (Co-codamol)
What are the adverse effects of codeine ?
Adverse effect: constipation, no euphoria (rarely addictive)
Codeine is a prodrug, where is it processed and what does it become
Prodrug is demethylated in the liver by CYP2D6 enzyme into morphine
What percentage of the population is resistant to codeine and why?
10% population resistant to effects of codeine
Genetic polymorphism causing these pipo to have poor metabolisers in liver to process the prodrug into morphine
Opioid analgesics arerelatively ………in dental pain.
Opioid analgesics arerelatively ineffectivein dental pain.
Which 3 drugs are adequate for most cases of dental pain (opioid is rarely required)
Paracetamol, NSAIDs (ibuprofen), or aspirin
Why was Dihydrocodeine firsted developed?
Developed as an antitussive to reduce the spread of tuberculosis
What is the potency of Dihydrocodeine relative to morphine
Defined as a weak semi-synthetic opioid analgesic:
20% analgesic potency of morphine. - similar to codeine (partial agonist)
When is dihydrocodeine used?
What is the common dose ?
Used for moderate-to-severe pain
(30 mg dose, every 4-6 hours)
What is dihydrocodeine commonly combined with and what does it form?
Analgesic preparations can be combined with paracetamol (Co-dydramol), Aspirin or NSAIDs
Advantage over codeine, metabolites unimportant: even poor metabolisers have good response to dihydrocodeine
Adverse effect: constipation, nausea and vomiting, pruritus (histamine release)
What are the advantages of using dihydrocodeine over codeine?
The advantage over codeine, metabolites are unimportant since it’s not metabolites in the liver CYP2D6: even poor metabolisers have a good response to dihydrocodeine
What are the adverse effects of dihydrocodeine
Adverse effect: constipation, nausea and vomiting, pruritus (histamine release)
Use of Opioids in compound analgesics:
Why do we combine compound analgesics with opioids?
- What is the rationale
Compound analgesic preparations that contain a simple analgesic (such as aspirin or paracetamol) with an opioid component to –> reduce the scope for effective titration of the individual components in the management of the pain of varying intensity.
Rationale: co-administration of two drugs that produce analgesia by different mechanisms
What are the 3 benefits of combining compound analgesics with opioids ?
- Additive effect so less of each drug is given to produce the same degree of analgesia
- Reduce the intensity of producing unwanted side effects by each drug
- Combining a non-opioid with an opioid analgesic can provide greater relief of pain than either analgesic given alone
With dental and orofacial pain when do we get an analgesic effect with combination analgesic preparations?
In dental and orofacial pain:
this applies only when an adequate dose of each analgesic is used
most combination analgesic preparations do not provide greater relief of pain
What are the 3 common compound analgesics and opioid combinations
- Codeine/Paracetamol =
Co-codamol - Dihydrocodeine/Paracetamol =
Co-dydramol - Codeine/Aspirin = Codis
With dental and orofacial pain combination preparation analgesics have what type of effect? and what should be done instead
combination preparations have the disadvantage of increasing opioid-induced side effects
an adequate dose of the non-opioid component given alone is usually sufficient
How did we confirm that opioids were having an effect on the body
when we discovered they were binding to μ (Mu) opioid receptors by using 3H-naloxone an antagonist - 1973 Pert and Snyder
Which structural component of naloxone allows it to have an antagonistic activity
Bulky substitution on the nitrogen atom of morphine introduces antagonist activity
Name 3 Naloxone characteristics which make it a great opioid antagonist.
- Short-acting (rapidly metabolised in the liver)
- affinity for all classic opioid receptors – first pure opioid antagonist
- Rapid reversal of the effects of morphine and other opioids
Name 2 adverse characteristics of naloxone.
- Exacerbate clinical pain (e.g. following dental surgery)
- Little effect on pain threshold under normal conditions, BUT during heightened sensitivity to pain (hyperalgesia) under stress-induced or inflammation-induced analgesia (when endogenous opioids are produced) can increase pain because it prevents the opioids binding on the same receptors
What are the 3 main clinical uses of opioids?
Main clinical uses:
- Treat respiratory depression caused by opioid overdose
- The reverse effect of opioid analgesia, used during labour, on the respiration of the newborn baby
- Oral naloxonecan reduce opioid-related constipation (Oxycodone)
Name two additional opioid (μ-receptor) antagonists other than Naloxone
Naltrexone and Methylnaltrexone bromide (Alvimopan)
What is the half-life of Naltrexone
and what its MOA
Long-acting (half-life ~10 hours)
Similar mechanism of action to Naloxone
What are the 3 main clinical uses of Naltrexone
Main clinical uses
- Subcutaneous implant for ‘detoxified’ alcoholics/addicts – nullifies relapse
- Reduce alcohol consumption in alcoholics, since part of the ‘high’ of alcohol comes from the release of endogenous opioid peptides
- Treat pruritus (itching) in chronic liver disease (endogenous opioid peptide involvement
Can Methylnaltrexone bromide cross the BBB?
Does not cross BBB
Only effective in the periphery
What is the main clinical use of methylnaltrexone bromide
Main clinical uses:
Block opioid-induced constipation
Endogenous Opioids & Receptors:
Name the structural motif found in both endogenous opioids (Ones found in Morphine and ones found the body) — > allows the binding of the opioid to the receptor-binding sites
The receptor binding site on opioids resembles the ‘tyrosine residue’ motif in endogenous opioid peptides
Name the 5 endogenous peptides and rank them in order of Mu-opioids receptor agonist activity/affinity
- Beta- Endorphin
- Leu-enkephalin
3.Met-enkephalin - Dynorphin
5.Orphanin FQ/Nociceptin
What was the classical Opioid recepto terminology
Opioid receptor classical terminology:
μ, δ, κ
What is the new revised opioid receptor terminology?
Revised terminology:
MOPr (μ),
DOPr (δ),
KOPr (κ) and
NOPr (ORL1; recent)
What type of receptors are 4 types of opioid receptors ?
- All 4 are either Homomeric or heteromeric G protein-coupled receptors
- All 4 receptors are coupled to the G protein Gi/Go - inhibitory effects
Name all the endogenous opioids that act on these 4 opioid receptors.
All endogenous opioids include Endorphins, Enkephalin, Dynorphin and (Orphanin FQ or Nociceptin; recent)
How many opioid peptides do we have
Twenty or more opioid peptides, only 4 receptors
Name the one endogenous peptide that has an affinity/ agonist activity on the NOPr (ORL1) receptor
Orphanin FQ/nonciceptin
Dynorphin has the most agonist activity on which receptor
KOPr
Responses to morphine and thought to be mediated by which receptor ?
Responses to morphine and thought to be mediated by MOPr (μ)
Opioids bind to which receptor type causes dysphoria and hallucinations
binding to KOPr
Opioids need to bind to which receptor to get the catatonia effect
NOPr
Heroin is more souble than which opioid
morphine
crosses the BB. ore easily and more addicitve
What is Oxycodone?
What is its metabolism?
Strong μ-opioid receptor agonist (κ opioid-receptor agonist evidence uncertain)
Metabolism: liver by CYP3A4 (noroxycodone) & CYP2D6 (oxymorphone)
What Drug interactions does Oxycodone have?
Why was it designed?
drug interactions: inhibitors & inducers of enzymes
Semi-synthetic (from thebaine, an opiate alkaloid) replacement for diamorphine (heroin; Bayer stopped production)
Designed as an improvement to diamorphine – thought to have similar potency, less addiction
How is oxycodone formulated
slow release tablet, addicts grind up tablets (reformulated make it difficult to crush)
Oxycodone is a major drug of abuse where was is it commonly abused ?
Most commonly abused opioid in USA and Canada
What is Pethidine ?
What is used for ?
What its effect relative to morphine ?
Strong synthetic μ-opioid receptor agonist
Moderate to severe pain (less effective than morphine)
acute pain relief (quicker than morphine, more lipid soluble)
obstetric analgesia (labour pains)
peri-operative analgesia
diverticulitis (inflammation colon)
What was Pethidine first developed as?
First developed as a anti-muscarinic to treat the pain associated with biliary spasms (gallstones) or renal colic (kidney stones) in 1939
What are the negative effects of Pethidine ?
Produces tachycardia, dry mouth
- Its sister drug USA ‘meperidine’ was a major opioid used in the 1970’s/80’s - thought to be less addictive than morphine BUT it is as addictive as morphine and has little to no anti-muscarinic effects ABSOLUTELY USELESS
Where is pethidine metabolised
- In the Liver
- Metabolism: partly N-demethylated in the liver to norpethidine (hallucinogenic and convulsant effects
What are the contradictions of pethidine
CNS excitation or depression (hypertension or hypotension) when pethidine given with MAOIs - Monoamine oxidase inhibitors
additive anti-muscarinic effect
What is fentanyl?
Where was it dervived from ?
What are the 3 derivatives of fentanyl ?
Fentanyl (1960)
Strong synthetic μ-opioid receptor agonist
Derived from the structure of pethidine
Derivatives of Fentanyl: Alfentanil, Sufentanil, Remifentanil
Fentanyl potency
Potency:
100x more potent than morphine
500x more lipid soluble than morphine;
rapid onset
shorter duration than morphine
Name the 3 clinical uses of Fentanyl
Clinical uses:
enhancement of anaesthesia, severe chronic pain,
breakthrough pain
How is fentanyl administered
Via transdermal patches
What are the does available for the transdermal fentanyl patches
Transdermal Patch (Doses 12, 25, 50, 75, 100 µg/h)
72-hour Fentanyl patches ~ equivalent X hour doses of oral morphine:
12µg/h Fentanyl = X mg/24h oral morphin
72-hour Fentanyl patches ~ equivalent 24-hour doses of oral morphine
12µg/h Fentanyl = 30 mg/24h oral morphin
What are the 4 disadvantages of fentanyl
Disadvantages:
- slower onset of action: 8 – 12 hours
- rate of absorption affected: body temperature, skin type, fat, site placement
Fever- /external heat : increased side effects (respiratory depression)
- remove patch: breathing problems, confusion, drowsiness
Loperamide (imodium):
- What does it treat?
- Why doesn’t it have an analgesic effect?
- Which Mu-Opioid receptors does it act on?
- What potency level does it have relative to morphine?
- What therapeutic effect does it have?
Loperamide (1976: FDA approval)
μ-opioid receptor agonist:
Treats: acute diarrhoea, IBS
No analgesic activity: does not cross BBB (efflux by P-glycoprotein)
Acts on the μ-opioid receptors in the myenteric plexus of the large intestine:
decreases its activity (50x morphine),
Therapeutic effect: reduces smooth muscle tone, decreases GI motility, slows transit time so it enhances water/ion absorption
Why is loperamide poorly absorbed into circulation?
What 2 adverse effects does loperamide have?
Poor absorption into circulation:
P-glycoprotein pump back into the intestinal lumen
Enterohepatic recycling
Adverse effects: constipation, abdominal cramping
What is tolerance?
Which 3 methods can tolerance to a drug occur?
Tolerance: progressively decreased responsiveness to a drug upon repeated drug administration:
- an increase in the dose is needed to produce the original pharmacological effect
- loss of sensitivity to drug is developed quickly (a few days during repeated administration of drug)
- involves desensitisation of the μ-opioid receptor
What is Dependence?
What are the two types of dependence?
Give detail in regard to the symptoms
Dependence: state in which withdrawal of the drug causes adverse physiological effects (withdrawal syndrome)
whenever an opioid administered for more than a few days, comprises of two components:
Physical dependence: associated with the withdrawal syndrome and lasts for a few days (restlessness, irritability, runny nose, diarrhoea, abdominal cramping, nausea & vomiting, sweating, insomnia, shivering, piloerection, tachycardia, hypertension)
Psychological dependence: associated with craving and can last for months or years (rarely occurs in patients being given opioids as analgesics
What is addiction?
Addiction: behavioural pattern of drug use, characterised by overwhelming need to use a drug (compulsive use), securing its supply, and a high tendency to relapse after withdrawal
drug self-administration without making a distinction between physical or psychological dependence
Name the two opioids used for heroin withdrawal
Methadone and Buprenorphine
What type of opioid is Methadone?
What percentage of bioavailability does it have?
Methadone: potent synthetic µ-opioid receptor agonist, well absorbed with good oral bioavailability (75%)
what is the main use of methadone?
and why
main use: a substitute for opioids (heroin) in addicts due to its slow onset & offset
reduces the incidence of withdrawal symptoms from heroin, BUT methadone dependence can develop
What type of opioid is Buprenorphine?
What kind of efficacy does it have?
What effect does it have when combined with heroin?
Which other opioid is it combined with to manage opioid dependence?
Buprenorphine: potent semisynthetic µ-opioid receptor partial agonist (~25x more potent than morphine)
- low efficacy compared to full agonists, able to antagonist effects of agonists (heroin, morphine) at opioid receptors
- when heroin is injected ‘on top’ of buprenorphine, less euphoria is achieved
- marketed as sublingual preparation combined with naloxone for the management of opioid dependence
Morphine ions can get trapped in the brain what does this cause?
Morphine ions trapped in the brain which can potentially lead to increased toxicity
Morphine is a ____ base
WEAK base
what happens to morphine in the brain
becomes at ion - charged because it gains an H+ when it crosses the BBB because the brain is more acidic . so it then cant recross the bbb so its trapped
Morphine is extensively metabolised by the gut wall and liver into?
- Morphine-3-glucuronide (M3G) – 70%
- Morphine-6-glucuronide (M6G) – 10%
- Sulphate conjugates
What is the potency of the M6G relative to morphine
M6G is 10-20x more potent than morphine and is normally excreted in urine
Why can morphine be toxic in pts with renal disease
morphine metabolites, M3G and M6G, accumulates in renal failure and accounts for increased sensitivity to morphine
What is Neuropathic pain
Neuropathic pain is the severe, debilitating chronic pain that occurs in conditions such as neuropathy and trigeminal neuralgia (TGN; trigeminal nerve):
- What is neuropathic pain often thought to be?
- Name the new opioid drugs that are effective for neuropathic pain
-Name the anti-epileptic drug that is thought to be effective for neuropathic pain
It was often thought neuropathic is opioid-resistant
Newer opioids including Tramadol and Tapentadol can be effective
Antiepileptic drug, Carbamazepine is effective in TGN
Carbamazepine is used for which conditions?
- MoA?
Carbamazepine (Tegretol; Novartis)
It has been used as an anticonvulsant and antiepileptic in the UK since 1965
blocks voltage-gated sodium channels (VGNC) used to treat TGN
certain VGNC subtypes are upregulated by nerve damage & contribute to the sensation of pain
a GABA receptor agonist (inhibitory neurotransmitter)
Start 100 mg 1-2 times a days, titrate up to achieve effective response (in some cases 1.6–2 g daily in divided doses may be needed)
Use to differentiate dental pain from TGN
What dose is commonly given for carbamazepine
Start 100 mg 1-2 times a day, titrate up to achieve an effective response (in some cases 1.6–2 g daily in divided doses may be needed)
What is Tramadol ?
What are the 3 MoA of tramadol?
What is tramadol prescribed for ?
Tramadol is a synthetic analogue of codeine,
Triple mode of action:
- weak agonist µ-opioid receptor (similar to codeine and pethidine)
- weak noradrenaline uptake inhibitor
- weak serotonin uptake inhibitor
Most prescribed weak opioid in UK - moderate to severe pain
What are the side effects of tramadol?
tramadol contraindication ?
Side Effects:In equi-analgesic dose to morphine, tramadol produces less:
- respiratory depression
- cardiovascular depression
- constipation
BUT shares the most common side effects of opioids (e.g. vomiting, drowsiness)
Contraindication: in patients on MAOI or with a history of epilepsy.
What is Tapentadol ?
MoA?
What is the potency of tapentadol relative to oxycodone?
Most recent opioid analgesic, with dual action:
- agonist µ-opioid receptor
- weak noradrenaline uptake inhibitor
Potency: equal to oxycodone, greater then tramadol
What are the clinical uses of tapentadol ?
Clinical use:
moderate to severe pain for:
- Acute: following injury, surgery, etc.
- Chronic: musculoskeletal pain
Specifically indicated for controlling the pain of diabetic neuropathy
