Fun facts from morning CME: heroin overdoses are undercounted and morphine overcounted because heroin metabolizes to morphine
We’re all aware data for opioids in chronic pain is bad, but turns out there is no good data for *any* long term treatment for chronic pain.
Most opioid trials for pain = “modest benefit” but people tend to have good benefit *or* negligible response so study average is misleading
Chronic pain conferred a higher risk of 10 year mortality than heart disease.
The three primary endogenous opioids are endorphins, enkephalins, and dynorphins. The three primary opioid receptors are mu, kappa, and delta.
Endorphins are “natural painkillers” and induce feelings of well-being. Enkephalins inhibit emotional and physical pain signals.
Dynorphins live in the brain stem, spinal cord, and hypothalamus and regulate all sorts of stuff...circadian rhythm, stress-induced depression, drug-seeking behavior.
Opioid painkillers mostly bind mu opioid receptors reducing pain and causing euphoria.
Dynorphins bind kappa receptors => resp depression, spinal analgesia, dysphoria
Opioid analgesia => 1) direct inhibition of ascending transmission of pain signaling from dorsal horn of spinal cord and 2) activation of descending pain control circuits from midbrain to dorsal horn
Dialing in more: inhibitory G proteins activated, inhibits adenylate cyclase, reduces second messengers, inc K which counters Ca2+ influx, reducing depolarization of cell membranes and neuron signal pulses.
Because mu opioids are mostly active in central nervous system, they are less effective for peripheral neuropathic-type pain. But there are some kappa and mu receptors in the periphery.
The opium poppy is still the most prevalent source of opium and opioid analgesics. It’s been cultivated since 5000 BC. 🌺
Friedrich Serturner isolated morphine from opium in 1806. He nearly killed himself and three young boys he experimented on and did kill a dog with a morphine OD.
It’s tough to synthesize morphine from scratch. Opium poppies are still used to make morphine, codeine, thebaine, and papaverine.
Thebaine is made into oxycodone, oxymorphone, naloxone, naltrexone, and buprenorphine.
It’s fairly easy for chemists to make morphine into codeine and diacetylmorphine (heroin).
Laudanum was a tincture of 10% powdered opium dissolved in alcohol. It was 1% morphine. 
So opioid pharmacology and effects are monstrously complex and different from person to person depending on genetics, pain sensitization, experience, psychology, trauma history...
hydromorphone (dilaudid) is 5-7x as strong as morphine with more euphoria and possibly less sedation. Meta-analysis showed significant better pain control than morphine without sig diff in adverse effects.
Codeine is a pro-drug of morphine. However it is metabolized via cytp450 2D6 and there are a large % of poor metabolizes or ultra-rapid metabolizers out there.
Oxycodone is made from thebaine. It’s 20 times *less* potent at mu receptor than morphine, but has much higher oral bioavailability and also tickles the kappa 2b receptor.
Oxycodone is more rapidly transported past the blood brain barrier and results in less dysphoria than morphine. It was first synthesized in 1917. Purdue discontinued the 160mg pill in 2001 due to concerns of abuse...
Hydrocodone (as in lortab or vicodin) is a pro-drug with complicated metabolism, but roughly ends up being similar potency-wise to codeine.
Hydrocodone is good for cough suppression and moderate pain...usually comes in combinations with acetaminophen and NSAIDs. It’s thought to give a more stable, slow release with less euphoria.
Methadone is entirely synthetic, first made in Germany in WWII when they couldn’t get their hands on opium poppies.
High dose methadone blocks other potent mu receptor agonists, thus its utility in medication assisted treatment for addiction.
(The dose isn’t discussed here but i was always taught the dose that blocks other opiates is 60mg and above per day)
Methadone has a racemic form with two enantiomers: l(R) is a mu receptor agonist and d(S) is an NMDA receptor antagonist and SNRI. (Editorial: So don’t taper too fast!!)
Methadone causes little euphoria and lots of analgesia. On the surface this sounds terrific...the big big downside is highly variable elimination half-life.
Methadone’s painkilling properties last *4-8 hours* but elimination half life is *8-60 hours*, so if you don’t pay attention and re-dose to pain you can accumulate methadone and OD.
Editorial: pain relief doses for long acting agents are TID but doses for detox are QD. However if tapering tid meds used for pain or anxiety best to taper dose, not frequency as a general rule. Works better. 😎
(By long acting agents I mean methadone for pain and Valium for anxiety) OxyContin is supposed to be bid but many folks needed tid...led to escalation of bid doses and increased predilection for addiction.
Fentanyl! Made originally in Belgium. 80-100 times as strong as morphine. Very lipophilic, scoots right through BBB and has quick onset of action. More potent painkilling with less potent nausea, sedation, urinary retention, itching than morphine or hydromorphone.
Fentanyl respiratory depression is similar to other mu agonists and quicker in onset. ☠️
Legal versions in US are IV for hospital use, mostly, trans mucosal sprays, transdermal patches...no fentanyl pills are legal in US.
Carfentanyl (or carfentanil) is a similar product smuggled in for selling for recreational use and very deadly, as most folks in high opioid use areas know already.
Tramadol (😖) is a synthetic codeine with SSRI/monoamine reuptake inhibitor. It’s pharmacology means it’s better for neuropathic pain and has a low abuse potential.
Editorial: Stop prescribing it with SSRIs and TCAs you’ve made three of my patients seize over the years. 🤬
Speaking of seizures, meperidine (Demerol) is in the same synthetic opioid family as fentanyl but is much weaker. 1/10th as potent as morphine.
Meperidine is short acting (2.5-3.5 hours) and apparently uniquely good for post-operative shivers. The neurotoxic metabolite normeperidine accumulates so DO NOT administer for more than 24 hours at high dose or 48 hours at any dose.
(In med school we used to use this for pre-op biliary colic because morphine could cause biliary spasm is that still a thing?)
DO NOT administer meperidine with MAOI or you will kill someone dead. Also normeperidine toxicity does not reverse with naloxone so keep that vent handy!
LAAM is a long acting methadone also made by Germans just after WWII. It can prevent opiate withdrawal for 3 days but also caused such extensive QT prolongation it was pulled from the US market in 2004 (geez I’m old).
Now my favorite, the partial agonists (for the noobs en.wikipedia.org/wiki/Partial_a… )
Buprenorphine blocks most other mu agonists while partially activating the mu receptor, so it can stop abuse of many other opioids and stop withdrawal at the same time.
It will *cause* immediate withdrawal if you administer it to someone opiate-dependent so needs some training for proper use. It is also addictive on its own but escalating doses aren’t a thing (because it’s a partial agonist).
No doses higher than 32mg (ime 16mg) are any more effective than lower doses for cravings/wd, and the dose ceiling for pain is 15mg.
It’s illegal to prescribe for detox or dependence without special training and waiver from DEA. It’s legal for anyone with unrestricted DEA license to prescribe for pain (usually transdermal for pain).
Main risk of buprenorphine is respiratory depression when combined with benzos.
Sooooo the holy grail would be an opiate with painkilling effect but no euphoria, addiction potential, or respiratory depression. Mixed agonists/antagonists with this in mind were developed and are used in cancer pain (butorphanol, talwin, nubain).
The mixed agents developed so have not achieved this opioid holy grail.
Now the antagonists!! These are used for respiratory depression in OD, addiction, and opioid induced constipation. We have naloxone (narcan), naltrexone, and methylnaltrexone.
Super low dose naltrexone has some interesting and unexplained properties, such as enhancing other opioids and maybe helping symptoms of fibromyalgia, autism, or allergies and other autoimmune dx (off label but you will see it mentioned in review articles)
Methylnaltrexone (relistor) is that expensive med you see advertised for opioid induced constipation. It’s an opioid antagonist in the gut.
Other random opioids you may have heard of or used...lomotil and Imodium bind GI opioid receptors to cause constipation in cases of diarrhea. No significant central effects.
Metabolism section in this CME is next (we already covered a lot of that) but wanted to add that methadone is also increased by 2D6 and 3A4 inhibitors and reduced by the inducers.
Of course tramadol 😖 is also partially 2D6 so watch out with Wellbutrin and all these too: ildcare.eu/Downloads/arts…
(I should say no significant central opioid effects! See @skipbidder ‘s tweet)
Some final useful links: CDC guidelines for opiates for non-cancer chronic pain guideline.gov/summaries/summ…
FYI Some folks find the doses in these recommendations too arbitrary and based on ED dosing recommendations for nontraumatic acute pain.
Respiratory depression and ODs often occur in combination with other CNS depressants.
Older folks can have delayed absorption, reduced metabolism (liver and kidney), and decreased receptor density with increased receptor affinity.
Opioid-induced hyperanalgesia: pain is amplified paradoxically. Suspect when unusual or unexplained pain without new injury or pain to normally non-painful stimuli.
It is probably caused by NMDA receptor activation and increased spinal cord dysnorphin levels that activate pro-pain neuropeptides and CNS glial cells (inflammation).
This pain (while caused by chronic or increased opioid dose) is similar to the pain described in opioid withdrawal so probably has a similar mechanism.
Morphine most likely to do this, methadone least likely (as an NMDA antagonist as well), lowering dose, switching to methadone, or reports of using ketamine (also NMDA antagonist) can be useful.
Different pain responses to different opioids are approx 25% genetic. That’s p450 enzymes, COMT enzymes, transporters, cytokine gene promoters, and kappa and mu opioid receptor polymorphisms.
(So patients don’t always not respond to your favorite pain med post op because they want to annoy you and wake you up in the middle of the night on call).
Main opioid side effects: euphoria, sedation, nausea, constipation. More rare: respiratory depression, itching, delirium, dependence, addiction, neonatal withdrawal, immunosuppression hypogonadism (methadone >> buprenorphine)
C’est tout. This was by no means a comprehensive thread, just some interesting facts! Now I have to go walk my puppy.
