OPIOIDS : Principles of opioids and optimizing outcomes Flashcards
Pharmacokinetics
- What the body does to the drug
-
ADME
- Absorption
- Distribution
- Metabolism
- Excretion
Pharmacodynamics
What the drug does to the body
*
Factors that affect pharmacokinetics of opioids
- Age
- metabolism, volume of distribution, reduced in elderly
- increased free concentrations in plasma
- hepatic flow declined
- increased CNS sensitivity
- Hepatic disease
- Unpredictable
- severe failure = marked sensitivity
- reduction in plasma protein = increased plasma concentrations of drugs
- Renal failure
- renally cleared metabolites accumulate
- Obesity
- volume of distribution larger, longer half life, elimination
- Hypothermia, hyperthermia, hypotension, hypovolemia
- variable absorption
Pharmacokinetics : Absorption
- across lipid cell membrane
- passive process concentration gradient
- occurs in small bowel
List causes of altered absorption
- delayed gastric emptying
- medications that delay emptying (opioids, ach)
- sustained release formulations need to stay in small bowel to be fully absorbed
- may be reduced absorption if increased GI transit (maxeran, domperidone)
Pharmacokinetics : Bioavailability
- percentage of drug that gains access unchanged to systemic circulation
- oral administration most relevant
- Extensive first pass metabolism in liver
- low bioavailability of some drugs
- differences in bioavailability = challenges in safe dose selection between oral and parenteral
List reasons that can alter bioavailability
- hepatic dysfunction
- exposure to drugs that induce or inhibit P450 system
- eg:
- chronic liver disease, blood shunted from portal to venous system
- bypasses hepatic enzymes and first pass effect
- increased bioavailability of drug
Pharmacokinetics : Distribution
- volume of distribution :
- theoretical volume for total amount of drug needed to be uniformly distributed to achieve targeted blood concentration
- Volume for lipophilic drugs can be 4-5x body size
High volume of distribution
- drugs leaves plasma and goes intro extravascular components of body
- higher dose required to achieve blood concentration
- longer half life elimination
Low Volume of distribution
- more likely to stay in plasma
- lower dose required
- shorter half life
List factors that affect the volume of distribution
- acid base disturbances
- basic drugs tend to be more lipophilic
- leave systemic circulation, higher volume distribition
- acid drugs like albumin and bind to it, stay in plasma
- Lipophicility of drug
- higher VD
- Hydrophilic meds stay in plasma
Diffusable fraction of opioids
- proportion of opioid that is unbound to plasma proteins
- capable of diffusing to site of action
- determines speed on onset of clinical effect
- concentration of diffusable fraction
- lipid solubility
- diffuses across BBB
Compare onset of action and reason for morphine and fentanyl
- Morphine:
- high diffusable fraction, low lipid solubility
- slow onset
- Fentanyl
- high diffusable fraction, high lipid solubility
- fast onset
Pharmacokinetics : metabolism
- occurs in liver
- Phase I reactions :
- oxidation, reduction, hydrolysis, isomerization
- Oxidation catalyzed by CYP450 family of enzymes most important
- Phase II reacions:
- conjugations, glucoronidation, methylation
- goal is to produce water soluble products that can be excreted by kidneys
Pharmacokinetics : Elimination
- Liver
- Kidneys
- Clearance is volume of blood completely cleared of drug in unit of time
- determines half life and steady state
Pharmacokinetics : define Half Life
- measure of time taken for half the drug in the body to be removed
- correlates closely with duration of action
Concerns:
- long half life accumulates for prolonged period of time
- concentration can surpass effective therapeutic range
- toxicity
Pharmacokinetics : Steady State
- 5-6 half lives requried to reach steady state
- regardless of route of adminstration
- aim is to achieve intended effect without side effects
- swings between trough and peak:
- amount depends on eliminimation half life and frequency of administration
How much time does it take to reach steady state?
- depends on half life
- 5-6 half lives
- 95% of steady state drug concentration achieved with 4 half lives.
- relevant for first order kinetics (most drugs)
- Eg: half life of morphine is 2-4 hours.
- given q4h
- steady state 95% will be at 4x4 hours = 16 hours
- can titrate every day then to ensure dose changes are at steady state
Pharmacodynamics
- drugs produce effects by:
- binding with receptors
- modifyign enzyme processes
- direct chemical or physical actions
Opioid receptors
- Mu (MOR)
- kappa (KOR)
- delta (DOR)
- ORL-1 Orphan
- opioid like receptor
- (nociceptin peptide receptor NOR)
- spinal cord
- modulates stress response, movement, etc
List endogenous opioids
- Encephalins
- Endorphins
- Dynorphins
Mu Opioid receptor
- Gene OP3
-
Expression
- CNS (cortex, thalamus, hypothalamus, periaqueductal gray, amygdala)
- Spinal cord
- Peripheral nervous system
- Immune cells
- Endogenous ligand
- beta endorphin
- encephalins
- endomorphins
-
Function
- inhibits nociceptive pathways
- all exogenous opioids can bind
- analgesia
- resp depression
- reduce GI motility
- mioisis
- euphoria
- sedation
- dependence
Kappa Opioid Receptor
- Gene OPRK1
- Expression:
- CNS, same as Mu
- no amygdala
- spinal cord
- PNS
- Endogenous ligand
- Dynoprhins
- Function
- modulation of pain
- chemical and visceral and thermal pain
- analgesia
- responsible for lots of side effects
- nausea and vomiting
- dysphoria
- mioisis
- dysphoria
- hallucinations
- sedation
Delta Opioid Receptor
- Gene OPRD1
- Expression
- CNS (cortex, striatum, olfactory bulb)
- PNS
- Endogenous ligand
- encephalines
- betaendorphins
- Function
- analgesia
- resp depression
- reduced GI motility
- tolerance
- mood regulation
Opioid AGONISTS
- binds to cell receptors to induce changes in cell that stimulate physiological activity
- no ceiling effect to analgesia
- log linear function of analgesia until either analgesia or adverse side effects occur
- most opioids are Full agonists
- morphine,
- HM,
- oxycodone,
- methadone,
- fentanyl
Partial AGONISTS
- low intrinsic efficacy
- lack of linear response in analgesia after dose escalation
- ceiling effect at less than maximum effect compared to full agonist
- Buprenorphine

Potency
- dose response relationship
- intensity of effect of different drugs
- equianalgesic effects
- ratio of doses of 2 analgesics required to produce the same effect
- by convention, it is compared to 10 mg IV morphine

Efficacy
- maximal reponse by active drug
- degree of analgesia after dose escalation through a range limited by adverse effects

Opioid Mixed agonist / antagonists
- Agonist effects at one receptor
- Antagonist effects at another
- Eg. Nalbuphine
- Pentazocine
- when mixed antagonist-agonist is given with an agonist, the antagonist effect at mu receptor can cause withdrawal.
Opioid ANTAGONISTS
- Interfere with action of agonist
- have no pharmacological action intrinsically
- competitive antagonists bind to same receptors as agonists
- non competitive antagonists block in other ways
- Eg Naloxone, Naltrexone
List GI Side Effects of Opioids
- nausea
- constipation
- dry mouth
- vomiting
- Ileus
List CNS side effects of opioids
- Somnolence
- COnfusion
- Myoclonus
- Nightmares
- hallucinations
- hyperalgesia
List GU side effects of opioids
- Urinary retention
List respiratory side effects of opioids
- decreased cough
- respiratory depression
List skin side effects of opioids
- diaphoresis
- pruritis
List Endocrine side effects of opioids
- Hypogonadism
- Immunosuppression
Define Adverse drug effect
- unwanted or harmful reaction to drug
- when given under normal circumstances
- suspected to be related to drug
Pharmacokinetic drug interactions
- changes in rate and extent of absorption
- rate of metabolism
- distribution
- renal exretion
Common drug interactions
- GI tract
- metoclopramide, ACh alter gastric emptying
- alters speed of absorption
- drugs that bind in GI tract (PPI, iron, cholestyramine) : decrease bioavailability
- Liver
- changes in bioavailability
- miss first pass metabolism
- decreased clearance
- CYP450 interactions
- inducers/inhibitors
- Kidney
- loop diuretics compete for active tubular secretion
- NSAIDS
What happens if you give buprenorphine with Morphine?
- morphine induced analgesia reversed or limited by competetition of partial agonist buprenorphine.
Immediate and Sustained Release
- IR:
- absorbed in stomach and small bowel
- complete in 1-2 hours of ingestion
- SR
- smoother concentration profile in blood
- extended duration and reduction in pill burden
Transmucosal administration
- avoids first pass metabolism
- higher bioavailability
- faster onset of action
Transdermal
- Lipid soluble drugs well absorbed through skin
- caution in cachexia and fever
Opioid pharmacogenomics
- CYP2D6 allele
- genetic polymorphisms
- 4 phenotypes
- poor metabolizers (10% caucasions, no analgesia)
- intermediate
- extensive
- ultra metabolizers (3%, adverse effects, toxicity)
- CODEINE partially metabolized by CYP2D6
- Fatal neonatal opioid toxicity in children breastfed by mothers who are ultrarapid metabolizers
Mixed mechanism Drugs
- Tramadol / Tapentadol
- centrally acting anaglesics
- Mu agonist AND monamine SE, NE reuptake inhibition
- ceiling dose
WHO Analgesic ladder for Cancer Pain
Step 1 Mild Pain
- non opioid +/- adjuvant
Step 2 Moderate Pain
- Weak opioid +/- non-opioid +/- adjuvant
Step 3 Severe Pain
- Strong opioid +/_ non-opioid +/- adjuvant
Why do some clincians prefer to omit the second step of the WHO ladder and move directly to step 3?
- Improved understanding of the metabolism of codeine
- Wider range of step 3 opioids available. Can use low dose of these
- Low dose strong opioid more efficient than switching mutiple times
Codeine
- naturally occuring opium alkaloid
- low affinity for mu receptors, bioavailability 60-90%
- metabolized to morphine
- codeine 6 glucoronide
- M3G and M6G
- CYP 2D6 with ++ genetic polymorphism
- 1/2 life 2 hours, peak 1.5-2 h, duration 3-6h
- dose 30-60 mg po
Oxycodone
- semi-synthetic congener of morphine
- high oral bioavailability 60-90%
- metabolized to oxymorphone in liver (not active)
- pure mu agonist
- more potent than morphine (1.5 :1)
- accumulates in renal failure
- CYP 3A4 and CYP 2D6
Tramadol
- CYP 3A4 and 2D6
- Mu agonist
- Monoamine inhibitor (Serotonin and NE)
- Modest affinity for mu, weak affinity to delta and kappa
- can be reveresed by naloxone
- ceiling effect
- Side effects similar to morphine
Tapentadol
- mu agonist
- NE reuptake inhibitor
- minimal 5HT inhibition
- no active metabolites, no drug drug interactions
- CI with MAOI
- limited evidence
Morphine
- potent mu agonist
- liquid, IR, CR
Absorption
- Absorption is complete in upper small bowel
Metabolism
- pre systemic first pass metabolism in liver
- bioavailability 20-30%
- t1/2 2-3 hours, duration 4-6 hours
- rectal bioavailability similar to oral
- M3G - no analgesic effects
- does not bind to mu receptors
- M6G - active metabolite, binds to opioid receptors
- potent analgesic
- may cause toxicity
Excretion
- liver first pass
- Kidney excretes metabolites
Other
- Hydrophilic
- epidural this means no systemic absorption, long 1/2 life in spinal fluid. extensive rostral redistribution
Morphine potency and conversions
- 1:3 or 1:2 IV: oral
- Single dose vs chronic dosing
- M6G accumulation may be greater with oral than parenteral administration
Sustained release morphine
- peak of 3-6 hours
- duration 12-14 hours
- do not use for titration period
Methadone
- Synthetic opioid at mu receptor NMDA receptor antagonist
- oral : parenteral potency 1:2
- single doses, potency similar to morphine
- repeated doses = increased potency
- half life 12-150 hours with variability
- Steady state 1 week
- Ratios:
- 4:1 MEDD < 90
- 8:1 MEDD 90-300 mg
- 12:1 MEDD >300 mg
Meperidine
- synthetic opioid
- mu agonist
- active metabolite is norpethidine:
- twice as potent as a convulsant
- half as potent as analgesic
- accumulates ++ with repeated dosing
- CNS excitability, mood , tremor, myoclonus, seizure
- naloxone not effective for seizures, may even preciptate seizure by blocking anti seizure action of meperidine
- Accumulation in renal function
- 5HT4 syndrome with MAOI combination
- NOT USEFUL IN CANCER PAIN
Hydromorphone
- semi synthetic morphine congener
- 5x as potent at morphine
- potency ratio:
- equianalgesic ratio for parenteral HM : M differs
- 7:1 when going morphine to HM
- 4:1-8:1 when going HM to morphine
- Oral equianalgesic ratio
- 7.5-1
- IV hm : oral HM 1:2
- equianalgesic ratio for parenteral HM : M differs
- mu agonist
- high concentrations available for sc infusion
- Metabolism:
- oral bioavailability 60-80%
- partially metabolized in liver
- H3G metabolite
- largely excreted unchanged in liver
Fentanyl
- semi synthetic opioid
- highly selective mu agonist
- 100X as potent as parenteral morphine
- ++ lipophilic
- rapid onset 3-5 minutes
- duration 30-60 minutes
- t 1/2 3-12 hours (longer with repeated administration –> fat sequestration)
- NO active metabolites
- some evidence less constipating
Transdermal fentanyl
- TD absorption bc low molecular weight and high lipid solubility of fentanyl
- serum {} increases gradually, levels of at 12-24 hours
- after removal, serum [] falls to 50% at 17 hours
- avoid in patients with unstable pain
- subcutaneous depot of drug that maintains plasma concentration
Rotating to patch
- takes 8-12 hours to get analgesia
- need to continue IR original opioid until then
Patch placement
- minimal skin movement
- cachexia may not absorb
- no heat pads
- watch for fever
- cold = less absorption
When you might choose a fentanyl patch
- loss of oral route (head and neck ca, obstruction)
- poor compliance with po meds
- opioid toxicity or intolerance of other opioids
- stable opioid dosing
- patient preference
Avoid if unstable pain
++ Education when starting
Oral Transmucosal fentanyl
- Lozenge
- Rapid absorption
- Onset 5-10 minutes
- Good for incident pain
- Dose is not dependent on MEDD
Also can be given :
- sl
- nasal fentanyl spray (esp for kids)
When should opioid therapy be initiated?
- moderate or greater pain
- regardless of mechanism (neuropathic, somatic, visceral)
- dose titration until analgesia or side effects
Buprenorphine
- PARTIAL mu agonist
- true partial mu agonist
- ceiling effect in higher doses
- oral not effective as all elimated in first pass metabolism
- injectable, sl, patch
- single doses of 0.3 mg iv are equal to 10-15 mg morphine IM
- LONG duration of action (6-9 hours)
- onset 30-60 minutes
Nalbuphine
- mixed agonist-antagonist
- produce analgesia in opioid naive, but withdrawal in people already dependent on opioids
- mu ANTAGONIST, and kappa AGONIST
- Not useful for repeated dosing for pain, limited role
- low incidence of euphoria or respiratory depression
- useful for opioid induced pruritis
Factors to consider when selecting an opioid
- Pain severity
* opioid vs non-opioid - Pharmacokinetic formulations
- start with a shorter half life opioid
- oral route if possible, or IV/sc
- Co-existing disease
- renal impairment
- hepatic impairment
- Response to previous opioids
Rectal administation
- morphine, hydromorphone, oxycodone
- may be different from oral admin
- bioavailabilty might be different
- bypasses first pass hepatic metabolism
Parenteral administation
- Bolus effects:
- toxicity at peak concentration
- breakthrough pain at trough concentrations
- IV bolus most rapid onset, depends on lipid solubility
Epidural / Intrathecal dosing
- opioid receptors present in dorsal horn of spinal cord
- Epidural 1/10 of MEDD
- Intrathecal 1/100 MEDD (or 1/10 of epidural dose)
Sublingual administration
- bioavailability poor with less lipophilic drugs
- works for SL fentanyl, buccal methadone, buprenorphine
Scheduling opioids
- Around the clock
- start low and go slow
- IR formulations, then SR
- Morphine 5 mg po q4h, HM 1mg po q4h, oxycodone 2.5 mg po q4.
- Breakthrough dosing
- q1h po or q30 min IV/sc
- usually same as regular opioid (except methadone and fentanyl
- 10% daily dose
- or 1/6 of 4 hourly dose of opioid (ie same as 4 hourly dose)
- If more than 3 breakthrough doses/day, consider titration of base opioid
Titration
- log linear increase in analgesic compared to dose
- escalations of < 30-50% are not likely to improve analgesia significantly
Opioid tolerance
- Tolerance to analgesic effect:
- need for increasing doses to maintain same effect in the abscence of other factors that would explain increase in pain.
- true tolerance is less common than disease progression or psychological distress
- true tolerance is from changes at receptor level.
- Tolerance to side effects varies:
- Respiratory depression, somnolence, nausea RAPID tolerance
- Constipation SLOW Or NO tolerance
List side effects of opioids that resolve quickly (tolerance develops rapidly)
- somnolence
- nausea/vomiting
- respiratory depression
- urinary retention
Opioid Rotation
- dose reduction of 25-50% for incomplete cross tolerance
- to reduce toxicity, overdose, and minimize underdosing.
- Always done to reduce opioid side effects.
- Usually improves :
- cognition
- delirium
- sedation
- myoclonus
- nausea/vomiting
List common opioid adverse effects
Gastrointestinal
- nausea/vomiting
- constipation
Autonomic
- xerostomia
- urinary retention
- postural hypotension
CNS
- sedation
- cognitive impairment
- hallucinations
- delirium
- respiratory depression
- myoclonus
- seizure
- hyperalgesia
Cutaneous
- Itch
- sweating
Endocrine
- hypogonadism
- impaired adrenal hormones - blunted stress reponse
- obesity - diabetes
List factors that predict opioid adverse effects
- Drug related
- fentanyl less constipating
- Route related
- Patient related
- age
- renal function (M6G)
- hepatic function
- Other drugs
- Dose related
- CNS side effects increased with increased dose
- GI effects weaker dose reponse
- constipation universal and not related to dose
Approach to treating adverse effects
- Rule out other causes of adverse effects
- Then consider
- Dose reduction 25%
- if pain is well controlled
- use of non opioids or adjuvants
- targeted therapy : radiation, chemo, surgery
- regional anesthesia, blocks, etc
- Specfic therapies to treat AE
- Opioid rotation
- Change route
- switching routes from po to sc may help
- poor evidence
Differential diagnosis of opioid adverse effects : delirium/drowsiness/cognitive impairment
CNS:
- mets
- leptomeningeal disease
- CVA
- extradural bleed
Metabolic
- dehydration
- hyper CA
- Hyper/hypo NA
- Renal failure
- hepatic failure
- hypoxemia
Sepsis/infection
Iatrogenic
- tcas
- benzos
- NSAIDS
- chemo/rads
Differential diagnosis of opioid adverse effects : nausea/vomiting and constipation
Bowel obstruction
Medications:
- antibiotics
- vinca alkaloids (constipation)
- Flutamide (constipation)
- NSAIDS
- chemo/rad (nausea and vomiting)
Metabolic
- hyper Ca
- Hyper/hypoNA
Management of opioid induced constipation
- prophylactic laxative (PEG, senna)
- does not improve with time
- avoid bulk laxatives
- methylnaltrexone
Management of opioid related nausea and vomiting
- Often resolves over days-week
- opioids stimulate CTZ, delay gastric motility, delayed emptying
- either prn antiemetic effective at CTZ (prokinetic)
- scheduled prokinetic if nausea persistent
Management of confusion and delirium related to opioids
- Discontinue all non essential centrally acting medications
- If analgesia satisfactory, reduce opioid dose by 25%
- Exclude sepsis
- Exclude CNS tumour involvement
- If delirium persists, consider neuroleptic, rotation, change in route, different analgesic options.
Management of sedation related to opioids
- sedation typical wehn beginning opioid therapy or dose increase
- tolerance within days to weeks
- limited evidence to treat with methylphenidate if persistent
- rotation may help
- opioid sparing adjuvants (rads, interventional)
Respiratory depression related to opioids
- can be early indicator of CNS toxicity
- tachypnea and anxiety never related to opioids
- tolerance develops rapidly
- respiratory depression can occur if pain eliminated suddenly (neurolytic, epidural)
High risk
- rapid titration
- high dose
- pre -existing underlying lung disease
- multiple opioids given suddenly
Management:
- supportive with 02
- naloxone with caution, Titrate to RR
- naloxone infusion if long acting
- if peak effect already reached and patient bradypneic but rousable, can simply hold next dose and monitor
Naloxone
- pure mu antagonist, displaces opioids at receptor
- IV/IM/SC/intranasal
- Dosing:
- IV/SC/IM 0.4-2.0 mg single dose –> withdrawal
- 0.02-0.2 mg for patients with opioid tolerance/dependence IV/SC/IM
- 20 ug IV push
- Continuous infusion
- 2/3 of effective bolus dose given hourly
- 0.25-0.6 mg/hour
Myoclonus from opioids
- can be normal, very common
- If distressing/frequent, consider dose reduction or rotation
- can treat with benzo (clonazepam) or gabapentin
Hypogonadism secondary to opioids
- chronic opioids inhibitis HPA axis
- interferes with GnRH
- lower levels of LH and FSH
- clinical presentation:
- fatigue
- muscle wasting
- Erectile dysfunction
- reduced libido
- menstrual changes
- vaginal dryness
- Can consider HRT
Metabolism and opioids
- Weight gain
- Hyperglycemia
- Worsening DM
- Central action of sympathetic nervous system and impaired insulin secretion
Urinary retention and opioids
- Opioids increase smooth muscle tone
- bladder spasm or urinary retention
- increased sphincter tone
- Tolerance develops rapidly
- cath prn
Opioid induced hyperalgesia
- paradoxical increase in reported pain with increasing or high doses of opioids
- central sensitization
- Management:
- dose reduction
- opioid rotation
- genetic variation in opioid respose
- differentia binding at receptor subtypes
- NMDA antagonist (methadone), etc
Opioids and driving
- provincial guidelines
- no driving while dose is titrated or initiated
- once sedation has resolved and dose stable, may resume driving
- self assessment by patient
Opioid Allergy
- morphine and other opioids can induce histamine release from cutaneous mast cells (asthma, urticaria)
- pseudoallergy and adverse effect
- rarely life threatening
- commonly morphine, codeine, meperidine
- rare : fentanyl, sufentanil, tramadol
- True allergy rare (< 2%). IgE mediated:
- anaphylaxis
- urticaria
- EM
- severe hypotension
- bronchospasm, edema
- angioedema
- difficult to distinguish, testing challenging
- assume likely pseudoallergy
- can switch to another class with less histamine release
- concurrent H1/H2 blocker can be considered
Opioid misuses and addiction
- Abuse :
- intentional self adminstration of medication for non medical purpose or use of illegal drug
- Addiction:
- primary chronic disease
- impaired control over drug use, compulsive use despite harm, craving.
- Risk of developing addictive behaviours with medical use of opioids for palliative care needs is low
- We overestimate risk of addiction
- confuse physical dependence and addiction
- reluctance to prescribe and use them
Therapeutic dependence
- Patient require a specific drug to control a disease process or symptom are dependent on therapeutic efficacy of drugs in question.
Psychological dependence
- effects mediated in CNS most likely to lead to misuse.
- continued craving and abherrent drug seeking behaviour
- use despite harm to self or others
Physical dependence and Withdrawal
- withdrawal when abruptly discontinued or opioid antagonist administered.
- Withdrawal:
- anxiety
- irritability
- chills/hot flashes
- salivation, lacrimation, rhinorrhea, sneezing, sweating
- nausea
- abdo cramping
- insomnia
- Time course of withdrawal function of half life of opioid
- Abstinence sx within 6-12 hours, peak at 24-72 hours for short acting opioids
- Sx onset 36-48 hours for long acting (methadone)
- must decrease / taper dose.
- usual daily dose to prevent withdrawal if 75% of previous daily dose
Pseudoaddiction vs addiction
- pseudoaddiction :
- intense concern about availablity of opioids an drug seeking behaviour
- resolves once pain is relieved with dose escalation
- addiction
- does not resolve.
Screening for misuse and abuse risk
- all patients should be screened
- validated tools (self report) : SOAPP, COMM
- require multidisciplinary team to manage