Help! MU receptors, descending, ascending, oxycodone, Levorphanol

[finis]

Background: Pain Mgmt Dr switched me from 20mg oxycodone 4/day to Levorphanol 2mg 3/day. Within a week I began no appetite, extreme diarrhea, very high blood pressure then restless leg syndrome. It took 5 weeks to get back to Pain Mgmt Dr. He screamed at me saying Levorphanol cannot cause the symptoms. I suggested oxycodone withdrawal, he said impossible since Levorphanol is an opioid, but allowed me oxycodone 15mg 3/day, and threatened dropping me as uncooperative and referred me to a psychologist.
i called the pharmacist who prescribes Levorphanol, the drug being sent from another state to my residence, who tried to explain that Levorphanol is an ascending synthetic opioid for nerve pain and oxycodone is a descending opioid for other pain and therefore I was going through oxycodone withdrawal. Then he went into MU receptors and lost me.
i took one-half of a 15mg oxycodone (it took 4days to get it filled due to shortages)and the diarrhea stopped.
So I am now back on the oxycodone regime. Stopped the Levorphanol 4 days ago. There is a train running through my head.
Can someone explain the ascending, descending, MU receptors in layman?s terms? And, with the doctor switching me out and back what this may be doing to my brain. I want to know what to expect in the coming weeks. I feel like I?m dying and I don?t care. Any help would be appreciated.

 

[Hodor]

The mu opioid receptor ("MOR") is the receptor that's selectively activated by morphine (and most other opioids, including oxycodone). Activating this receptor results in a strong analgesic effect, but also significant euphoria and respiratory depression.
To decrease the risk of addiction or overdoses, you would thus try to use substances whose pharmacological action synergizes with the pain-killing effects of mu agonism, but not its undesirable side-effects.

A popular example of this would be tramadol, which not only activates MOR, but also blocks the reuptake of serotonin and noradrenaline (noradrenaline reuptake inhibitors have been shown to be effective for certain forms of chronic pain). Methadone is an MOR agonist, but likewise increases its analgesic effect by activating the NMDA receptor. Pentazocine activates the kappa opioid receptor (KOR) instead of the mu receptor, which can produce pain-killing effects, but does not have the abuse potential of a selective MOR ligand due to the unpleasant side-effects that appear when used in higher doses.

Levorphanol is pretty much all of the above rolled into one: Due to the combination of its SNRI, NMDA antagonist and KOR agonist effects, its pain-killing effects are significantly stronger than what you would expect if you only considered its action at the mu receptor.
On the flipside, after being on 80mg of oxy for an extended period of time, your body is used to a constant activation of your mu receptors. A person without opioid tolerance might find 80 mg of oxycodone and 6 mg of levorphanol to be similarly effective for their pain, but due to your tolerance towards MOR agonism, your body is going to experience temporary withdrawal symptoms, as your mu receptors are just not getting activated anywhere near as much as they used to be.

Does it make more sense like that?

 

[Hodor]

Re: ascending and descending, that refers to different neural pathways involved in pain perception.
Normal mu-selective opioids apparently work mostly via the ascending pain pathways, while some of levorphanol's extra effects (SERT/NET inhibition, NMDA antagonism) also involve descending pathways.

 

[Hodor]

Or, to boil down my first answer as much as possible:

On oxy, all your pain relief used to come from mu receptor activation, meaning you got a hefty dose of euphoria and constipation with it.

On levorphanol, only part of your pain relief comes from mu receptor activation. This means that despite providing the same level of pain relief, there is less euphoria and constipation - and for an opioid-tolerant patient, this naturally means they will experience withdrawal symptoms like dysphoria and diarrhea.

 

[adder]

The problem is that your dose of levorphanol was too low. Levorphanol oral bioavailability is ~50%, oxycodone oral BA is around 80%, levorphanol is around 5 times as potent as oxycodone on a weight basis leaving bioavailability issues aside, so the maths is simple here, to substitute for 20 mg of oxycodone, you'd need 1/5*(80/50)*20 mg of levorphanol which is 6.4 mg. Cross-tolerance between the two opioids is not 100% so a little less might do, but still, what you were prescribed was thrice too low of a dose to substitute for your oxycodone dose. Levorphanol has a longer half-life than oxycodone so you would indeed need to dose it less frequently.

 

[Hodor]

so the maths is simple here

I'd say that when you're dealing with a massively different half-life between the 2 compounds, not to mention significant inter-patient variability regarding the analgesic efficacy of levorphanol, the math is anything but simple. Since OP would be taking the levorphanol 3 times a day, the drug is going to accumulate in his system, leading to a relatively high steady-state concentration after a few days - so comparing the potency based solely upon the effects of a single dose would be rather misleading.

That said, I do agree that his levorphanol dose was pretty low to begin with. The info I've found on switching from morphine to levorphanol recommends an initial dose conversion ratio of 15:1 to 12:1 in terms of the total daily (oral) dose. So 6 mg/day of levorphanol would be an adequate for someone on 72-90 mg of oral morphine per day. At 80mg/day of oxycodone, OP was taking the equivalent of 120mg of morphine, so their initial levorphanol dose should probably have been 8 to 10mg per day (and those conversion ratios usually try to err on the conservative side).

Unfortunately, levorphanol is extremely costly, so while it is a very promising treatment option, an adequate dose may also be prohibitively expensive for many patients with a high level of opioid tolerance