Shared Flashcard Set


Pharmacology Test 4

Additional Science Flashcards






  • Opioids are natural or synthetic compounds derived from Papaversomniferum poppies.  
  • Opioid agonists produce morphine-like effects (analgesia, euphoria, sedation, resp depression). 
  • All drugs in this category bind to specific opioid receptors in the CNS and PNS to produce effects that mimic the endogenous opioids (endorphans, enkephalins, and dynorphins).


How Do We Pharmacologically Treat Pain?




Topical Analgesics:


Ibuprofen-containing gels


Capsaicin ointments (Zostrix™)






volt.-gated ion channels & neurotransmitter systems targeted to inhibit pain


Non-opioid analgesics:



(1)Classic NSAIDs






Opioids analgesics:


Mimic actions of endogenous opioids in two ways:


Raising pain thresholds


Altering CNS perception of pain

For moderate to sever pain, opioids, alone or in combination with non-opioid analgesics are the gold standard for treating pain.


Opioids are most effective for three general types of pain:
  • Acute pain
  • Chronic pain
  • Pain flares


Opioids are typically not as effective for neuropathic pain unless given in combination with other analgesics (AEDs, antidepressant, NSAIDS)



Acute Pain


occurs suddenly as a result of an injury, surgery, disease, or other disorder. Usually sharp or intense, lasting from hours to days or weeks.


usually goes away once the injury is healed or the disease/disorder improves.


can become chronic if not properly treated and lasts a long time.


Chronic Pain


ongoing, or persistent, pain that lasts long after an injury or other disorder is expected to be healed.


Cancer pain is often chronic, but the exact cause of most chronic pain is unknown.


Chronic pain may come and go, but generally is any pain lasting >3 - 6 months.


Pain Flares


sudden increases (flare ups) in pain that may be due to activity (such as dressing, walking, or coughing) or unknown cause. A pain flare comes on quickly without warning, can be quite intense, can occur many times during the day and last minutes to hours.


Breakthrough pain” is a type of pain flare that overcomes or “breaks through” the daily medicine already being taken to relieve persistent pain.




Opioid Sites of Action for Analgesia:







Limbic system (greatest concentration of opioid receptors localized in the Amygdala; role is not believed to be analgesic, but mediate emotional response to pain)


Medial Thalamus (mediates poorly localized pain, emotionally influenced)


Hypothalamus (receptors here effect neuroendocrine secretion)


PAG (midbrain processing center, high concentration of opioid receptors, modulation of pain response in descending endogenous pain suppressant pathways)


Brainstem  (mediates respiration, cough reflex, nausea & vomiting, BP maintenance, pupillary response, and stomach secretions)


Spinal Cord (receptors in substantiagelatinosa involved in receipt and integration of incoming sensory signals leading to attenuation of painful afferent stimuli.)


PNS (peripheral sensory nerve fiber& terminals.  As in CNS, the decrease calcium-dependent release of excitatory, pro-inflammatory substances (Substance P) from nerve endings, which may explain anti-inflammatory effects of opioids)


Immune Cells (causes release of histamine from mast cell which leads to goose-bumps, sweating, bronchconstriction and vasodilation.  Role in analgesia unclear.)




  • Opioid agonists activate the endogenous pain-suppressant neural system.
  • Opioid agonists stimulate opioid receptors, whose endogenous activators are the opioid peptides, which serve as chemical messengers in the pain-suppressant neural system.
  • Neurotransmitters in EPSNS:norepinephrine, serotonin, enkephalin, dynorphan, endorphans





  • Multisynaptic pathway descends from somatosensory cortex to dorsal horn (DH).
  • PAG: key modulator of pain transmissions w/ higher influences.
  • Opoioid activation inhibits release of pain transmitters, stimulates endogenous opioid release, and causes excitation of inhibitory DH projection neurons.
  • THE ENDOGENOUS PAIN SUPPRESSANT NEURAL SYSTEM:a multisynaptic pathway from the midbrain periacqueductal gray (PAG) descending to the dorsal horn of the spinal cord.  Neurons in the system use norepinephrine, serotonin and opioid neuropeptides as neurotransmitters. When activated, the pain suppressant neuronal system reduces pain perception by preventing release of nociceptive neurotransmitters and inhibiting projection neurons in dorsal horn of spinal cord.





  • Drugs that enhance the action or prevent the degradation of NE and serotonin in CNS can have analgesic effects
  • Opioids inhibit release of pain transmitters (Glutamate & Sub P) and inhibit firing ascending projection neurons pre- and post-synapticallyin DH.
  • To better understand the diversity of actions of opioids, must understand the opioid receptor families.
  • PHARMACOLOGICAL KEY CONCEPTS:  Drugs that enhance release or prevent degradation of norepinephrine and serotonin in the CNS (e.g., some antidepressants, amphetamine and related drugs) can produce analgesic effects, probably by increasing action of these transmitters in the Pain Suppressant Neural system. Some antidepressants are useful in some pain conditions.
  • At the PAG,  Mu opiate actions block the release of GABA from tonically active interneurons causing an activation of PAG outflow,activation of forebrain and spinal monoamine receptors thatprovide sensory input to higher centers and mood. Stimulation of the PAG in the midbrain also activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem. 5-HT (serotonin) released from the raphe nuclei descends to the dorsal horn of the spinal cord where it forms excitatory connections with the "inhibitory interneurons" located in Laminae II.




Neurotransmitters in EPSNS:
  • norepinephrine,
  • serotonin, 
  • enkephalin,
  • dynorphan,
  • endorphans
Opioid Receptors:
  • G-protein coupled receptors
  • mu receptors
    Endogenous agonist:ß-endorphin;
    analgesia, respiration, GI
    Agonist-induced internalization
  • delta receptors
    Endogenous agonist: Met- and leu-enkephalin
    analgesia, GI
    Agonist-induced internalization
  • kappa receptors
    Endogenous agonist: dynorphin
    analgesia, hallucinations
    No agonist-induced internalization
  • N/OFQ receptor: orphan receptor
    o high sequence homology
    o very low or no affinity for binding conventional opioid ligands
    orole in opioid physiology remains unclear.
  • All coupled to inhibitory G-proteins which inhibit adenylyl cyclase (AC), increased K+ efflux, and reduced Ca2+ influx.



  • psychotic like behavior (halucinations, dysphoria)
Useful Opioid Receptor Mnemonics


Mu agonists: PEAR


(Physical dependence, Euphoria, Analgesia, Respiratory depression)



Kappa agonists: SAM, SAD, or SAP


(Sedation, Analgesia, Miosis)


(Sedation, Analgesia, Diuresis)


(Sedation, Analgesia, Psychotomimesis)




Delta agonists: ARGH


(Analgesic, Releases Growth Hormone)


Slide 14
Slide 15
**Mechanism of Action
  • Opioids decrease excitability by increasing K+conductances and decreasing neurotransmitter release: coupled to Gi/Go inhibitory proteins
  • Mechanism Of Action = Inhibit adenylyl cyclase (AC), increased K+ efflux, and reduced Ca2+ influx.


  • The mu, delta and kappa  receptors in endogenous neuronal settings are coupled, via pertussis toxin–sensitive G proteins, to inhibition of adenylyl cyclase activity, activation of receptor-linked K+ currents, and suppression of voltage-gated Ca2+ currents.



  • TOP  PANEL:  Opioid agonists stimulate the 7-transmembrane G-protein-coupled µ-opioid receptor on the postsynaptic neuron (top panel). This initiates steps that reduce the release of neurotransmitters (e.g., glutamate, acetylcholine, norepinephrine, serotonin, substance P) and promote the efflux of potassium, which leads to hyperpolarization and hence reduced cellular excitability. In the central nervous system (top panel), these actions reduce the transmission of pain,


  • LOWER PANEL:  In the gastrointestinal (GI) tract (lower panel), stimulation of μ-opioid receptors causes changes in gut motility and water secretion and absorption that may result in constipation and contribute to the development of postoperative ileus. In the GI tract, alvimopan blocks the binding of opioid agonists to the μ-opioid receptor and helps prevent constipation. Because alvimopan is largely unable to cross the blood-brain barrier, it does not block μ-opioid receptors in the central nervous system or interfere with centrally mediated opioid analgesia. Illustration by TainaLitwak, CMI.


  • G-coupled inward rectifying Potassium channels (GIRK) channels are gated following the activation of GPCRs associated with pertussis toxin-sensitive G proteins (Gi/o) that directly gate the channel (blue). The phospholipid PIP2 is closely associated with the channel to stabilize its functional integrity.


**Pharmacology of Opioid Agonists


  • Opioid agonist drugs exert the same pharmacological effects in both the CNS & periphery, but differ in their pharmacokinetic properties.
    • e.g., lipid solubility, latency to onset, duration of action, potency, ability to cross blood-brain-barrier, activity at different receptors, oral/parenteral potency ratio (e.g., oral availability), analgesic efficacy (none more efficacious than morphine).




**Opioid Pharmacokinetics




readily absorbed from the gastrointestinal tract, nasal & rectal mucosa, lung, transdermally, subcutaneous, intramuscular, or intravenous routes.




Approx 1/3 of morphine is protein bound, not stored well in tissue.  Accumulation in fatty tissue after frequent high-dose admin of highly lipophilic opioids should be remembered  (ie., fentanyl) due to their slow metabolism


CNS is primary site of analgesic and sedative effects.




conjugation with glucuronicacid in liver. The two major, still active, metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide




eliminated by glomerular filtration, primarily as morphine-3-glucuronide


For most opioids, >90% is excreted in first day.  Duration of action for most opioid analgesics is approximately 3-5 hours.


Fentanyl transdermal patch is very popular for post-surgical and cancer pain.  Although GI absorbtion is rapid, some opioids given po are subject to 1st pass metabolism by glucuronidation in the liver.  In such cases, the oral dose is required is much higher than the parenteral dose to get the same effect.  Since codeine & oxycodone are not easily conjugated  due to their methyl substitution at c3, they have high oral:parenteral potency.


Use of opioids in pregnant females must be done with caution since (1) the opioids readily cross the placenta and 92) in neonates the BBB for opioids is effectively lacking.  Opioids in near term or newborn animals can severly depress respiration.






  • Prototype Strong Opioid  Agonist for Moderate-Severe Pain
  • Short duration of analgesic action(~ 4-6 hrduration)
    m receptor agonist
    Active metabolite: morphine-6-glucuronide
    MS Contin ®: 12 -hrduration (controlled release)
    Various oral and parenteral forms
    Patient controlled analgesia (PCA)
    Hydrophilic, so  can spread
Pharmacological Actions of Morphine:


Analgesia – altered perception of pain and increased pain threshold.


Euphoria – powerful sense of contentment and well-being believe to be due to stimulation of ventral tegmentum.


Respiratory Depression – decreased responsiveness of medullary respiratory centers to PCO2;


- seen at both therapeutic and toxic doses. 


- most common cause of death in acute opioid overdose.


Nausea/vomiting – stimulation of chemoreceptor trigger zone in area postrema


worsened by movement, suggesting vestibular component.



Pharmacological Actions of Morphine:




Antitussive –  suppression of cough reflex


doesn’t correlate with either analgesic or respiratory depressant efficacy.


dextrometorphan (DM) and codeine more widely used antitussive opioids




Miosis  – most opioids (except meperidine) constrict the pupil as a result of m- and k- opioid receptor stimulation. 


Morphine excites the Edinger-Westphal nucleus of the oculomotor nerve, which constricts circular muscle due to enhanced parasympathetic stimulation.


Little tolerance develops to this effect.



Cardiovascular – At normal doses, vasodilation.  At high doses, bradycardia and  orthostatic hypotension.  Together with respiratory depression and increased PCO2, cerebral vessels dilate and CSF pressure increases.


Thus, morphine is contraindicated in patents with brain injury.



Histamine release – causes mast cells to release histamine resulting in urticaria, sweating, vasodilation and bronchoconstriction.


Morphine requires close monitoring,or should be avoided, in asthmatic patients.


IMPORTANT DIAGNOSTIC ALLY:  Pinpoint pupil is important diagnostically because most other causes of coma and respiratory depression cause dilation of the pupil.




Pharmacological Actions of Morphine:

Continued (again)



Hormonal changes:


inhibits release of GNRH & CRH


increases antidiuretic hormone (ADH) which worsens urinary retention.



Smooth muscle effects:


GI – decreased peristaltic contractions of large intestine & increase tone of anal sphincter results in constipation.


no tolerance develops


used to treat diarrhea and dysentery.


Uterus – decreased contractions


Urinary tract – increased tone in bladder, ureters & sphincter caused difficult urination.


Bile duct – spasms of spincter of Oddi may cause epigastric distress/biliary colic.


Bronchial – safe at therapeutic doses in healthy patients, but risk for aptients with compromised respiratory function (e.g., asthma, COPD, emphysema, etc.)

Inhibiting release of gonadotropin releasing hormone (GNRH)  and corticotropin releasing hormone (CRH) decreased luetinizing hormone, FSH, ACTH, and beta-endorphin, testosterone, and cortisol.




hydromorphone (Dilaudid®)


  • For moderate-severe pain 
  • m opioid agonist 
  • Short duration of analgesic action ~ 4-6 hrduration
  • Used perioperatively & in patient-controlled post-op analgesia or to reduce coughing reflex
  • Oral and parenteral forms 
  • Highly lipophilic, so can stay localized


fentanyl (Innovar® or Actiq ®) and related products


  • For moderate-severe pain 
  • m receptor agonist, highly lipophilic 
  • Short duration of analgesic action ~ 4-6 hrduration 
  • extremely potent (µg doses) 
  • widely used peri-operatively and for patient-controlled analgesia 
  • iv, intrathecal, epidural, transdermal, & transmucosalforms 
  • rapid onset and short lasting


**methadone (Dolophine ®)




  • For moderate-severe pain
  • Strong m receptor agonist, NMDA receptor antagonist
  • Longer acting (t1/2 = 15-60 h), orally active
  • Used post-op and in cancer pain
  • maintenance Rx in opioid dependence
  • Oral and parenteral forms
  • Can induce Long QT Syndrome
  • Methadone is difficult to use as an analgesic because of complicated pharmacokinetics, and differences in timing and duration of analgesia vs. respiratory depression, which can lead to accidental overdoses.











Methadone is rarely, if ever, indicated for treatment of acute pain… and should only be prescribed by clinicians who are familiar with its risks and appropriate use and are prepared to conduct the necessary careful monitoring.


Longer half-life results in slower development of tolerance and dependance


The additional mechanism of action (Nmda antagonist) also important for preventing tolerance




Detox of Heroin Addicts:  5-10 mg, po 2-3 times daily for 2-3 days… after d/c mild but endurable withdrawal syndrome.

Maintenance of Heroin recidivist, tolerance to 50-100 mg/day methadone is deliberately produced so that the addict experiences CROSS TOLERANCE to heroin (addiction-related reinforcing effects are reduced.)

Clinical Implications of Methadone


Detox of Heroin Addicts:  5-10 mg, po 2-3 times daily for 2-3 days… after d/c mild but endurable withdrawal syndrome.


Maintenance of Heroin recidivist, tolerance to 50-100 mg/day methadone is deliberately produced so that the addict experiences CROSS TOLERANCE to heroin (addiction-related reinforcing effects are reduced.)


oxycodone (Roxicodone ® and others) 
  •  For moderate-severe pain
~4 hr duration


m receptor agonist


Used  in post-op and cancer pain, other chronic pains


Oxycontin ® is continuous release w/ 12 hr duration


Oral forms only; available alone and in combinations (e.g., with aspirin (Percodan®), acetaminophen (Percocet®), ibuprofen (Combunox®)

When used properly, the OxyContin tablet must be taken whole and only by mouth. If the tablet is crushed, the controlled-release mechanism is defeated and the oxycodone contained in the tablet is all released at once. If the contents of an OxyContin tablet are injected intravenously or snorted into the nostrils a potentially lethal dose of oxycodone is released immediately. The risk of death due to abuse of OxyContin in this manner is particularly high in individuals who are not tolerant to opioids.





meperidine(Demerol ®)


  •  For moderate-severe pain
~2-3 hr duration


k agonist and magonist


Significant anti-muscarinic effects  (may worsen tachycardia)


Typically for short courses of treatment for acute, moderate intensity pain


Oral and parenteral forms


Adverse interaction with MAO inhibitor antidepressants


unique and severe side effects from major metabolite (nor-meperidine)


serotonin syndrome, seizures, delirium, dysphoria


Especially in patients with renal compromise

No longer used as much




  •  For moderate-severe pain
similar to morphine in onset and duration; m agonist


Synthetic opiate similar to morphine


Acute and chronic pain


Much longer half life than morphine




codeine, hydrocodone*, tramadol





Weaker m agonists than morphine


Tramadol inhibits NE and serotonin reuptake centrally & only partially antagonized by naloxone.


These agents are commonly found in combinations with NSAIDS or acetaminophen


Tylenol with codeine ®


hydrocodone plus acetaminophen; hydrocodone plus ibuprofen


Ultracet ®: tramadol plus acetaminophen


New : tapentadol (Nucynta ®) a stronger tramadol





*prescribed most often


  • THE MODERATE/INTERMEDIATE OPIOIDS ( for mild-moderate pain)
  • Tramadol (ULTRAM) is a synthetic codeine analog that is a weak -opioid receptor agonist. Part of its analgesic effect is produced by inhibition of uptake of norepinephrine and serotonin. In the treatment of mild-to-moderate pain, tramadol is as effective as morphine or meperidine. However, for the treatment of severe or chronic pain, tramadol is less effective. Tramadol is as effective as meperidine in the treatment of labor pain and may cause less neonatal respiratory depression.



GI opioids




loperamide (Imodium ® )


Diphenoxylate  (w/low dose atropine in Lomotil ® )


Does not cross BBB






The cough opioid




Dextromethorphan (DM)


AAP: Furtherresearch on dosage, safety, and efficacy of these preparationsneeds to be done in children.







Chemical name, diacetylmorphine


a pro-drug for morphine


Analgesic drug with high liability for recreational abuse

Under the chemical names diamorphine and diacetylmorphine, heroin is a legally prescribedcontrolled drug in the United Kingdom, and is supplied in tablet or injectable form for the same indications as morphine is, often being preferred over morphine due to its lower side-effect profile. It is also available for prescription to long-term users as a form of opioid replacement therapy in the Netherlands, United Kingdom, Switzerland, Germany, and Denmark, alongside psycho-social care—in the same manner that methadone or buprenorphine are used in the United States or Canada[9][10]—and a similar programme is being campaigned for by liberal political parties in Norway.










The mixed opioid agonist-antagonists
Agonist action at kappa receptor for analgesia, weak antagonist actions (partial agonist) at m receptor


Main use is for post-op analgesia (oral or parenteral) due to short half life (~2-3 hours)


s.c. administration causes irritant effect so not recommended.


Dysphoria, hallucinations, psychotomimesis all common adverse effects


No therapeutic advantage over morphine, although may have decreased physical dependence and less respiratory depression (ceiling effect)

Great care must be taken when administering mixed agonist-antagonists o r parial agonists to patients that have received pure agonists because it will precipitate abstinence syndrome.





  • a mixed partial agonist/antagonist
  • Partial agonist at mu receptors; very weak antagonist activity
    Very slow dissociation from mu receptor conveys long duration of action
    Buprenex ®, post-op analgesic
    Soboxone ® (with naloxone), for Rx of opioid abuse
  • Opioids replaced and blocked by buprenorphine. – Buprenorphine competes with the full agonist opioids for the receptor. Since buprenorphine has a higher affinity (stronger binding ability) it expels existing opioids and blocks others from attaching. As a partial agonist, the buprenorphine has a limited opioid effect, enough to stop withdrawal but not enough to cause intense euphoria.
Slide 30

**Opioid’s Adverse Effects:




Severe respiratory depression


Euphoria & Sedation


Constipation & Urinary retention


Nausea & vomiting


Pupillary Miosis


Dysphoria, Hallucinations & Psychotomimesis


Prolonged QT interval (especially, methadone)


Elevated intracranial pressure




Physical Dependence


Lowered seizure threshold


Urticaria (Hives)

All of these effects are more pronounced in the elderly

One man’s trash is another man’s treasure



Important Drug Interactions with opioid analgesics




  • Meperidine (Demerol®) and other long-acting narcotic analgesics are contraindicated with MAO inhibitors due to high incidence of hyperpyrexic coma
  • Sedative Hypnotics & Sedating Antihistamines: Increased CNS depression, particularly respiratory depression, & enhanced analgesia 
  • TCA’s, Antipsychotics:Increased sedation; variable effects on respiratory depression
  • CNS depression is enhanced by other CNS depressants (ie., The depressant effects of morphine are enhanced by phenothiazines (neuroleptics), alcohol, benzodiazepines, monoamine oxidase inhibitors, and tricyclic antidepressants.)


  • Meperidine (Demerol) + MAO inhibitor = hyperpyrexic coma

    Low doses of amphetamines enhance analgesia for unknown reasons.

  • Hydroxyzine (antihistamine) also enhances analgesia.




naloxone (Narcan ® )




μ-opioid receptor competitive antagonist


poor oral efficacy,


short duration (1-2 hrs) after injection (relapse risk!!!)


drug of choice for acute opioid overdose







  • Pharmacodynamics (no tolerance develops to antagonist effects)
  • Single dose of naltrexone (100mg,po) will block injected heroin effects for up to 48 hours and decrease cravings.
  • In absence of agonist, antagonists are inert
  • In morphine treated patients, antagonist completely blocks effects in 1-3 minutes
  • In OD patients, antagonists will normalize breathing, consciousness, pupil size and GI effects.
  • In dependent patients (those chronically using and tolerant (ie, appear normal on opioids) antagonists will rapidly precipitate abstinence syndrome.















nalmefene  (ReVex ® )




competitive antagonists at μ- and κ-opioid receptor


Only available for iv administration, longer half-life (~8-10 hrs)


used for opioid overdose as well (derivative of naltrexone)

nalmefene  and naloxone  appeared to be efficacious, safe, and to yield similar clinical outcomes in double blind study of overdose patients



naltrexone (ReVia ®  and Vivitrol ®)




Well absorbed orally, may undergo 1st pass metabolism


Longer half-life (~10 hrs) and long duration of action


Used to treat alcohol and opioid dependence




Develops to analgesic, euphorant, respiratory depressant, antidiuretic, emetic, and hypotensive effects of opioid agonists.


Cross tolerance within receptor family, less tolerance develops to mixed opioids, no tolerance to antagonists


Starts after 1st use , but doesn’t manifest clinically until 2-3 weeks of frequent use.


Tolerance to sedating actions develops quickly.


Tolerance to respiratory depression can be marked.


Not much tolerance develops to GI effects.


Tolerance to analgesic effects


confounded by disease progression.


addressed by increasing the dose and/or adding other drugs.


Tolerance and Causes


  • Tolerance, loss of drug effect with chronic dosing. Couple of possibilties. Decoupling between gproteins and receptor. Or internalization of mu receptors


Cross tolerance within receptor family
  • less tolerence develops to mixed opioids, no tolerance to antagonists
Opioid overdose


The triad of coma, pinpoint pupils, and depressed respiration strongly suggests opioid poisoning.


The finding of needle marks suggestive of addiction further supports the diagnosis.



Opioid Overdose

Treatment Strategy



1.Ventilate patient


2.Administer opioid antagonist


Naloxone is drug of choice


Restores breathing


Can precipitate severe withdrawal


Shorter duration than opioids so care should be taken that patients do not slip into coma



Priscription Painkiller
  • refers to opioid or narcotic pain relievers, including Vicodin(hydrocodone), OxyContin (oxycodone), Opana (oxymorphone), and methadone.
Physical dependence


altered physiological state produced by long-term administration in which target tissues adapt and require drug for normal functioning. Discontinuation produces withdrawal or abstinence.


a state of adaptation…manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, …administration of antagonist

Dependence does not always entail addiction


Physical dependence: “Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”






decreased efficacy of a drug associated with long term administration



state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drugs effects over time. 




Drug abuse:




self administration of a drug that deviates from approved medical or social standards, and that has adverse consequences for individual


maladaptive pattern of substance use leading to clinically significant impairment or distress…








compulsive drug use associated with strong craving and  preoccupation with obtaining and using the drug for its rewarding effects, without regard to adverse effects


Characterized by… impaired control over drug use, compulsive use, continued use despite harm, and craving.


Strong potential for relapse even after abstinence.

Addiction: “Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.”


Addiction is a chronic disorder with a strong potential for relapse. This means users who are trying to get clean fall back into old patterns of drug use and abuse. Because opiates are so potent, they have a particularly high relapse rate. Strong cravings and other withdrawal symptoms can trigger relapse, even after a period of abstinence.


The Rewards Circuit
  • Opiates can enhance dopamine release in central reward centers
  • The rewards Circuits:  the mesolimbic DA projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), and to a lesser extent on its afferent and efferent projection areas such as medial prefrontal cortex (mPFC), amygdala, and ventral pallidum


Strong Flu-like symptoms


Piloerection; gooseflesh (going cold turkey)


Muscle tremor and twitches (kicking the habit)


Abdominal cramps and diarrhea


Increased heart rate, blood pressure






Physical dependence is associated with addiction in an abuse situation, BUT can develop in the clinical setting without addiction.



Addictive behaviors and physical dependence are rare with short term use of opioids (e.g., post-op) in patients with no history of drug abuse
Addictive behaviors are unlikely to develop with long term use of opioids to treat pain in patients with no history  of drug abuse.
we need more and better data.
Physical dependence can develop with long term use of opioids in the clinical setting
Don’t confuse with addiction or abuse;
Abuse is not associated with craving


Who's at Risk of Opioid Abuse and Dependence


Certain groups are more likely to abuse or overdose on prescription painkillers.


Many more men than women die of overdoses from prescription painkillers.


Middle-aged adults have the highest prescription painkiller overdose rates.


People in rural counties are nearly twice as likely to overdose on prescription painkillers as people in big cities.


Whites and American Indian or Alaska Natives are more likely to overdose on prescription painkillers


About 1 in 10 American Indian or Alaska Natives aged 12 or older used prescription painkillers for nonmedical reasons in the past year, compared to 1 in 20 whites and 1 in 30 blacks.




The Bottom Line


Opioids have the potential for abuse, but the actual incidence of abuse among properly medicated pain patients is low. 


Addiction rarely occurs among those who use pain relievers as prescribed; the risk of addiction exists when these meds are used in ways other than prescribed.


NIDA Position Statement 2001


American Pain Society
Consensus Statement


Inconsistent use of the terms addiction, dependence and tolerance often results in misunderstandings between regulators, health care providers, patients and the general public regarding the use of medications for the treatment of pain.”



“Because of this, pain is often undertreated and individuals stigmatized because of their use of opioids for medical purposes. 


ortant Clinical Considerations




1.Use of pure agonists with mixed agonist/antagonist will (at least) minimalize effectiveness and (at worst) will precipitate withdrawal.


2.Use in patients with head injury is contraindicated due to increased PCO2 caused by respiratory depression; increased cerebral vasodilation further increases intracranial pressure (can be lethal)


3.Pregnancy: chronic use of opioids during pregnancy may result in physiolgical dependence in fetus and neonate that will manifest into withdrawal syndrome postpartum.


In pregnant females use caution since (1) the opioids readily cross the placenta and (2) in neonates the BBB for opioids is effectively lacking. 


Opioids in near term or newborn animals can severely depress respiration.


4.Patients with impaired pulmonary function.


5.Patients with impaired hepatic or renal function.


6.Due to metabolism by liver and renal excretion, in compromised patients opioids and their metabolites can accumulate if levels are not monitored and dosing is not adjusted.


7.Patients with endocrine dysfunction (e.g., adrenal dysfunction (Addison’s disease) or hypothyroidism (myxedema)) can have prolonged or exaggerated responses to opioids.


8.Drug-Drug Interactions with sedative hypnotics (increased depression), antipsychotic tranquilizers (increased sedation and resp. depression), MAO inhibitors (hyperpyrexic coma, hypertension, serotonin syndrome)


9.Patients with epilepsy or history of seizures (e.g., see meperidine).


10.Patients with heart disease (e.g., see methadone) or tachycardia (e.g., see meperidine).



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