Analgesics Flashcards
Provide examples of NSAIDs
- ibuprofen
- naproxen
- diclofenac
- indomethacin
- piroxicam
Aspirin
Technically a NSAID (COX1 and COX2 inhibition),
Low dose aspirin is not used for pain (high doses can be used in some conditions such as Migraine)
Describe the mechanism of action of NSAIDs
- NSAIDs work by inhibiting COX-1 and COX-2 enzymes
- COX-1 are expressed in most tissues and platelets, primarily involved in tissue homeostasis, and responsible for producing prostaglandins involved in renal blood flow autoregulation, and platelet aggregation (1)
- COX-2 is induced in many inflammatory cells, and is responsible for prostinoid mediators of inflammation; activated by IL-1, TNHa, and other inflammatory cytokines
- They appear on the second step of the WHO ladder, and are considered simple analgesia
Antipyretic effects:
Temperature balance is regulated by hypothalamus,
NSAIDs rest this control returning it to normal point when fever is present
Do not alter normal temperature
Achieved by inhibition of prostaglandin production in the hypothalamus
Analgesic effects:
Used for mild to moderate pain caused my inflammation or tissue damage
Peripherally ↓ prostaglandin production that sensitise receptors to inflammatory mediators
aka role in therapy; no aspitin , esp kids
(1) also gastic cytoprotection, initiation of parturition
List the side effects of NSAIDS
- related to inhibition of COX-1 and COX-2
- CV: Rise in blood pressure, fluid retention, myocardial infarct, stroke (caution advised for patients with cardiovascular disease)
- GI: Upper abdominal pain, gastric erosions, peptic ulcers, oesophageal ulcers, GI bleeding, perforation. (Relative risk varies between different NSAIDs and is dose related). Selective COX-2 have less (but not none) GI complications. If a NSAID must be used and there is concern about GI bleed a proton pump inhibitor (PPI) may be co-prescribed to prevent (or atleast reduce the risk) of GI complications.
Of the NSAIDs, Diclofenac and Ibuprofen appear to have the lowest risk of GI complications (and are commonly used in practice)
- Renal: Renal impairment (risk is increased in elderly, perioperatively, pre-existing renal disease and coadministration with ACEI and diuretics (triple whammy) or co-administration with other nephrotoxic medications should be considered before prescribing.
- Skin:
Erythematous reactions
Urticaria
Photosensitivity
Stevens-Johnson Syndrome (rare)
- Lungs
Aspirin-sensitive asthma (5% of asthmatics)
Bronchospasm (does not occur with coxibs) - Liver: NSAIDs should NOT be prescribed to patients with severe hepatic impairment!!
Describe some precuations and considerations when prescribing NSAIDs
- if given with paracetamol should use a lower dose of NSAID
- triple whammy
- Low dose aspirin is not used for pain (high doses can be used in some conditions such as Migraine)
Unsafe in children due to risk of Reye Syndrome
Most commonly used as an antiplatelet for cardiovascular and neurological indications. - Do not stop low dose aspirin when using a NSAID (as the antiplatelet effect of NSAIDs is less reliable than low dose aspirin)
Compare NSAIDs and COX-2 inhibitors
No particular agent has been shown to be more effective than any other in pain and inflammation
If a patient does not respond to the first NSAID trialled, generally one or two other NSAIDs should be trialled before confirming non-response to NSAIDs.
Monitor response and do not continue if there is no benefit after trial of different NSAIDs
Topical NSAIDs are commonly used for the treatment of local musculoskeletal conditions
minimal systemic absorption –> safer than oral NSAIDs;
Only be useful for superficial sources of musculoskeletal pain.
Co-prescribing with paracetamol enables lower doses of NSAIDs
Use a PPI for patients on an NSAID who cannot stop therapy but are at risk of GI adverse effect
Describe COX-2 inhibitors mechanism of action
COX-2
Induced in many inflammatory cells
Responsible for prostinoid mediators of inflammation
Activated by:
Inflammatory cytokines
Interleukin-1
Tumour necrosis factor-⍺
List some examples of COX-2 inhibitors
- celecoxib
- meloxicam
Describe the side effects of COX-2 inhibitors
- same as NSAIDs but less GI complications
Describe the mechanism of action of paracetamol
- a first line, simple analgesic
- affects synthesis of central prostaglandins
- mechanism of action not fully elucidated
- has negligible anti-inflammatory effects
What are the indications for paracetamol
Fever, mild to moderate pain, adjunct to moderate to severe pain
What are the side effects of paracetamol?
Adverse Effects:
Uncommon
Occasionally skin reactions
Fatal hepatotoxicity in overdose
It does not have gastric or platelet AdvEs.
It is generally less effective than NSAIDs for MSK pain, but has a favourable safety profile, warranting a trial first line for mild to moderate pain
Also has use in reducing dose of other agents e.g. NSAIDs and opioid; reducing use ofNSAIDs and associated adverse events
Discuss precautions when prescribing paracetamol
- The maximum daily dose of paracetamol is 4g, but the dose should be reduced in frail older patients, or in people who have significant liver disease, are malnourished or fasting, or have a low bodyweight
- Patients with low body weight should be dosed as 15mg/kg/dose and a max daily dose of 60mg/kg/day.
- Toxic doses (10-15g) cause potentially fatal hepatotoxicity (delayed 24-48 hours later
- Saturates normal metabolising enzymes –> drug converts to toxic metabolite (N-acetyl-p-benzoquinone imine - NABQI) which is unable inactivated –> accumulation in the liver and kidney –> necrosis
Provide examples of opioids
oxycodone morphine fentanyl and hydromorphone*
Discuss the mechanism of action of opioids, including partial opioids
- Considered ‘strong’ analgesics and occupy the top rung of the WHO ladder
- An opioid is any substance that produces morphine like effects
- All receptors are G protein coupled receptors
- There are many opioid receptors but the mu receptor is the one MOST responsible for analgesia and all opioids act on this receptor (but many act on others too - which mostly contribute to the side effect profile)
Opioids promote opening of potassium channels and inhibit opening of voltage-gated calcium channels
- ↓ neuronal excitability
- ↓ transmitter release
- Inhibition at a cellular level
Majority of receptors located in the brain and spinal cord
OPIOIDS HAVE VERY LIMITED ROLE IN MUSCULOSKELETAL CONDITIONS
Discuss the opioid receptors and their actions
μ (mu)
- Responsible for most analgesic effects of opioids
- Adverse Effects: Respiratory depression, constipation, euphoria, sedation, dependence
δ (delta)
- Activation of this receptor can result in analgesia
- Proconvulsant
κ (kappa)
- Contribute to analgesia at spinal level
- Cause sedation, dysphoria, hallucinations
ORL1 (Opioid receptor like 1): activation has anti-opioid effects
Note: all opioids act on mu. But there is variability based on PK and PD. There can be a 10 fold variance in sensitivity; altered metabolism, sensitivity of receptors (tolerance), and genetic variance (e.g. CYP mutations)
Describe how PK/PD considerations can affect choice and dosing of opioids
Absorption: If the patient has acute pain and cannot tolerate oral medications they may need an injection eg intravenous (quick and 100% bioavailable) so would need to chose an opioid that can be given IV
Distribution: An opioid which is more lipid soluble (higher Vd) will more readily cross the BBB and therefore have a faster onset of action.
Metabolism:Most opioids are metabolised by CYP enzymes into either active or inactive metabolites. Codeine is a pro-drug that is metabolised to morphine - if a patient cannot metabolise the codeine they will not get the analgesic effect
Excretion:If a patient has renal impairment one would want to avoid an opioid that was cleared by the kidneys.
Specific receptor activity: Some opioids have activity on other receptros such as serotonin. If a patient is taking a medication that is already active at that receptor one might want to aviod an opioid with that activity
Tolerance:If a patient is usually on an opioid and they present with acute pain they will need a higher dose of the acute opioid due to the receptos being chronically occupied.
Describe some common opioid side effects
Respiratory depression
The most serious adverse effect of opioids; Sedation always precedes respiratory depression Supression of the respiratory centre in the medulla
Nausea and vomiting
May occur initially; an antiemetic may be given prophylactically, but review use within a few days as nausea often lessens with continued opioid use. Reduced gastric motility
Constipation
Start laxatives when beginning opioid analgesia. If patient is already taking laxatives, monitor and adjust or add laxatives if needed Little, if any, tolerance develops. Attention to fluid intake, diet and mobility is required; regular laxative use (eg stimulant laxative and stool softener) is essential as soon as chronic opioid treatment is started.
What opioids have additional transmitter activity?
Tramadol - has opioid and serotonin activity (serotonin-reuptake inhibition) as well as a small amount of noradrenaline activity (re-uptake inhibition). It is considered a WEAK opioid as it has less opioid receptor activity than other opioids.
Tapentadol - has opioid and noradrenaline activity as well as a small amount of serotonin reuptake inhibition. It is thought to cause less side effects and dependence compared with the traditional opioids (but is a relatively new drug so time will tell)
Methadone - Has NMDA receptor activity and is used primarily in opioid dependency as it has a long half-life and therefore less withdrawal symptoms.
Buprenorphine - Partial agonist (at mu receptor)
What are some practical considerations when prescribing opioids?
- An adjunct agent may be required, but will need specialist advice!
Changing opioids
- When changing drugs, consider equianalgesic doses. There may be incomplete cross-tolerance between opioids.
- Monitor closely and titrate dose depending on assessment of pain control.
Describe the mechanism of action of naloxone and naltexone
Naloxone:
- Pure opioid antagonist (competitive antagonist)
- Rapidly reverses effects of opioids
- Short acting (<1 hour), shorter than the duration of the opioid and therefore repeated doses (or continuous infusion) may be required
- Given intravenous or intramuscularly
- Not absorbed orally
Naltexone:
- Reversibly blocks opioid receptors (for 24–72 hours), preventing opioid effects, eg euphoria.
- Reduces craving for alcohol and possibly reduces some of the pleasurable effects, by blocking the effects of endogenous opioids
- Given orally
naloxone injection; naltexone oral, chronic mgmt of alc, opioid dependence
Describe the indications for naloxone and naltexone
- Opioid overdose or intoxication: as a diagnostic aid in suspected overdose, to avoid the need for assisted ventilation in opioid overdose
- Reversal of opioid sedation: as an aid to weaning from assisted ventilation in intensive care units, to reverse sedation/respiratory depression postoperatively
- Adjunct in treatment of alcohol dependence
- Adjunct in maintenance of abstinence from opioids after opioid detoxification
