Somatic pain in skin, subQ, and muscle

Visceral pain originating from thoracic and abdominal structures (responds best to opioids)

Neuropathic pain is usually caused by nerve damage (least responsive to opioids, but they can still be used)

Nociceptors on primary afferent (C - slow/dull or Ad - fast sharp)

Descending inhibitory pathways from periaqueductal grey/raphe and locus ceruleus inhibit ascending spinal thalamic tract neurons

Also activate interneurons in spinal cord that release met-enkephalin that inhibit release of pain mediators 

Sensory Ab fibers arising from peripheral tissues inhibits pain transmission via release of enkephalins from interneurons

Enkephalins - small peptides (leu and met) and are released from neurons in periaqueductal grey, medulla, and spinal cord 

Modulate neurotransmission by having an inhibitory effect 

Endorphins/dysnorphins are larger peptides 

Mu, delta, and kappa

Most useful analgesics activate mu receptors; some of the agonist/antagonist drugs work at kappa receptors 

Act through GPCR coupled to Gi 

Alpha subunit inhibits adenylate cyclase -- decreases cAMP 

B/Gamma increase K conductance -- decreases Ca influx

Inhibit both presynaptic and postsynaptic neurons

Analgesia, sedation/euphoria/dysphoria (action, serotonergic, dopaminergic and noradrenergic midbrain nuclei), miosis (tolerance does not develop), nausea/vomition (activate chemo trigger zone and enhanced stimulation of vestibular organ)

Respiratoy depression with decreased hypercapnic drive and no effect on hypoxic drive

Cerebral circulation will increase blood flow and increase cranial pressure (protons enter brain --> vasodilation)

Inhibition of cough reflex, truncal rigidity 

Tolerance with Opioids

How long does it take to develop? How do you minimize it?

Mechanism unclear, but may involve compensatory increase in cAMP, or endocytosis/degradation of the receptor, or receptor uncoupling 

Usually willl take 2-3 weeks but can occur quickly with large doses over short interval. Tolerance minimized by giving small doses at longer intervals 

Does not develop with miosis or constipation

No tolerance to pure antagonists 

Tolerance develops markedly to antidiuretic, emetic, and hypotensive, analgesic, sedating, and respiratory depressant

Cross tolerance particularly between those agents that activate mu receptors, but is often incomplete

Therefore, opioids can be rotated to maintain analgesia in cancer patients 

NMDA antagonists can slow down opioid tolerance 

Also, some studies using ultra low doses of an opioid antagonist can prevent tolerance 

Manifested if drug is taken away, therefore continued use of drug is needed for patient's wellbeing 

Symptoms: Rhinorrhea, lacrimation, yawning, chills, piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety/hostility 

Depends on half life of drug

Time of onset, intensity, and duration of withdrawal symptoms depends on opioid used

Morphine withdrawal symptoms peak in 36-48 hours whereas methadone withdrawal may take several days to reach peak and may persist as long as 2 weeks 

Antagonists like naloxone can precipitate a transient and explosive withdrawal within 3 minutes - can be used to diagnose or to reverse overdose (severe respiratory depression) 

Clonidine can also be used to terat some autonomic symptoms of withdrawal (reduces sympathetic)

Euphoria, indifference to stimuli, and sedation promote compulsive use; can also cause intense pleasure rush compareable to orgasm 

Despite risk of abuse, adequate pain relief should never be withheld 

Sedative hypnotics (benzodiazepines) - increase respiratory depression 

Antipsychotic, TCAs - will increase sedation, potential for increased CV effects 

MAOi - opioids release serotonin so can cause serotonin syndrome 

Barbituates - decrease their half life and will make opioids less effective 

Respiratory depression, miosis, coma 

Miosis isn't always present because some opioids have antimuscarinic properties (meperidine, pentaocine, diphenoxylate) 

Diagnose with naloxone 

Pulmonary dysfunction (except pulmonary edema)

Patients with closed head injuries (can increase cranial pressure)

Hepatic/Renal dysfunction (how drug is eliminated)

Adrenal or thyroid deficiences (prolongs sedative action)

Pregnancy (opioids can cross placenta) 

Partial agonists could precipitate withdrawal in patients tolerant to a full agonist

Specific, strong acting agent

Principal alkaloid of opium; diacetic ester of it is heroin

Well absorbed orally but significant first pass metabolism to 3-glucuronide (inactive); significant amount is metabolized to 6-glucuronide, which is more active and has longer half life

Standard to which other drugs are compared; used for severe pain of trauma, MI (coronary vasodilation and reduction of oxygen demand)

Fentanyl and sufentanil are synthetic opioid agonists (most potent)

Been formulated into long acting 

Fentanyl has been formulated into long acting transdermal skin patch for severe chronic pain

Used parenterally preoperatively and postoperatively and with general anesthesia too

AE: truncal rigidity 

Synthetic Opioid Agonist (Strong)

Drug has antimuscarinic properties so it may cause pupils to dilate 

Effects on smooth muscle are less pronounced than morphine, so it can be used for analgesia in obstetrics 

Orally used in outpatient for moderate to severe pain, but long term not recommended because of normeperidine: CNS excitation, convulsions, and tremors

Strong synthetic opioid agonist

Most often used orally for opioid dependence or chronic pain

Because long half life, administered once a day

Methadone used orally can prevent craving for heroin, but it does not cause significant euphoria or other reinforcing effects

Semisynthetic opioid morphine derivative (strong)

Used with NSAID to treat moderate to severe pain 

Sustained release is called oxycontin - it has caused several deaths because dependent people have crushed pill and injected it IV 

Moderate opioid agonist

Methyl group at 3-position (less first pass metabolism than morphine)

Converted to morphine via CYP2D6 - responsible for significant analgesic effect (genetic polymorphisms can either cause increase or decrease)

Used in combo with an NSAID to treat mild to moderate pain

Used in cough syrups as an anti-tussive, but not in children

Half analgestic property of codeine

Moderate opioid agonist

Recently taken off market because puts patients at risk of potentially serious or even fatal heart rhythm abnormalities (risk didn't outweigh benefits)

Specific opioid agonist

Weak agonist at mu receptors and inhibits serotonin and NE reuptake -- may potentiate descending inhibitory pathways (may be why TCAs used in pain)

Used for moderate pain and in chronic pain syndromes 

Abuse potential 

An analogue of codeine used as an anti-tussive

Minimal analgesic and addictive properties 

Abuse of its (powdered) form has been reported

Also use in children <6 y.o. banned because of reports of death 

Used for diarrhea in combination with atropine

Atropine is at too low a dose to have a therapeutic effect, but is thought to reduce likelihood of abuse 

Abuse potential is low 

Anti muscarinic properties 

Activates mu receptors in the periphery, not in the CNS

Its potential for abuse is low, so it's available OTC 

Produce less respiratory depression and are therefore safer at overdose

Less abuse potential

Less constipation 

Partial agonists can precipiate withdrawal in a patient who is dependent on a full agonist 

Mixed

Partial agonist at mu receptors and antagonist at kappa & delta

Slow dissociation from mu receptors - longer DOA than other parenteral opioids 

Less respiratory depression, but its affects can't be reversed by naloxone 

Also available orally and sublingually with naloxone to prevent IV abuse

Approved for outpatient treatment of opioid abuse

Relief of moderate to severe pain, also used post-op 

Mu antagonist/partial agonist and kappa agonist

Sedation nausea sweating

Used for acute pain relief

Available IV or intranasally

Mu antagonist/partial agonist and kappa agonist

Sometimes can cause anxiety, nightmares, psychotomimetic effects as a result of sigma receptor stimulation; nausea and sweating

Moderate to severe pain 

Oral (contains naloxone): used for moderate to severe pain or IV used as a preanesthetic or as a supplement to surgical anesthesia 

Will bind to opioid receptor but won't activate it

These drugs are used to treat overdose and treat opioid as well as other drug dependencies

Naloxone Naltrexone

Used IV to block respiratory depression of opioid agonist

It works within 30 seconds, but may need to be repeated if opioid agonist is long acting

Used in oral preparations of opioid agonists to prevent IV abuse

(not well absorbed orally so it won't have an effect unless it's IV)

Used to treat opioid dependence and alcoholism

Oral and transdermal preparations

Longer duration of action than naloxone (up to 48 hours)

AE: hepatotoxicity, nausea, sedation, and headache

Fentanyl, meperidine, methadone, morphine

Meperidine should not be used for more than a few days because of its toxic metabolite 

caused by trauma/surgery

Risk of producing dependence in these patients is low

Analgesic should be given at regular stages initially

Dose should control pain while minimizing sedation and side effects

Patient controlled analgesia allows patient to self administer a preset amount of opioid (fentanyl) via a pump interfaced with a timing device -- balances pain control with sedation 

Caused by a number of different conditions

Usually treated with opioid/non-opioid combo, coanalgesics, PT, psychotherapy, as well as transcutaneous nerve stimulation, local anesthetics, or capsaicin 

Risk of drug dependence and tolerance in these patients so be careful and make a contract with patient 

Transcutaneous electrical nerve stimulation (TENS), acupuncture, physical therapy

Antiepileptic Drugs: carbamazepine, gabapentin, phenytoin, valproate (probably works by inhibiting nerve conduction) --> trigeminal neuralgia, postherpetic neuralgia, continuous burning pain

Tricyclic Antidepressants - amitryptyline and desipramine. Used for postherpetic neuralgia, diabetic neuropathy, migraine, and other neuropathic pain 

Duloxetine: diabetic neuropathy

Tramadol: chronic pain syndrome 

Most patients can be managed with oral agents including opioids, NSAIDs, and neuropathic drugs

In severe cancer pain, it is necessary to use strong opoid agonists continuously via sustained release preparations or skin patches 

Acute pulmonary edema

Cough

Diarrhea

Anesthesia (most commonly in cardiac surgery because it does not cause as much depression