Tag Archives: Nonaddicting narcotic

What neuropharmacology can’t tell us about opiates and addiction

A friend’s wife had some painful surgery and is trying to get by with as little opiates as possible, being very worried about becoming an addict, something quite reasonable if all she had to go on was the popular press with lurid stories of hapless innocents being turned into addicts by evil physicians overprescribing opiates (it’s the current day Reefer Madness story). Fortunately her surgeon wisely told her that her chances of this happening were quite low, since she’d made it past 50 with no dependency problems whatsoever. Here’s why he’s right and why neuropharmacology can’t tell us everything we want to know about opiates and addiction.

Back in the day, disc surgery required general anesthesia, dissection of the back muscles down to the spine, sometimes chipping away at the bones of the spine to remove a bone spur (osteophyte) and/or removal of the offending herniated intervertebral disc. This meant a hospital stay (unlike my ophthalmologist who had a microdiscectomy as an outpatient a few years ago). This was the era of the discovery of the protein receptor for morphine and other opiates, and we were all hopeful that this would lead to the development of a nonAddicting opiate (narcotic). Spoiler alert — it hasn’t happened and likely won’t.

Often, I was the neurologist who diagnosed the disc and told the surgeon where it was likely to be found (this was in the preCT and later the preMRI era). I’d developed a relationship with most of those I’d referred for surgery (since it was never recommended, without a trial of rest — unless there were compelling reasons not to — trouble controlling bowels and bladder, progressive weakness etc. etc.). I was their doc while they tried to heal on their own.

So post-operatively I’d always stop by to see how the surgery had worked for them. All were on a narcotic (usually Demerol back then) as even if the source of their preoperative pain had been relieved, just getting to the problem had to cause significant pain (see above).

If the original pain was much improved (as it usually was), I’d ask them how they liked the way the demerol made them feel. There were two types of responses.

#1 I hate feeling like this. I don’t care about anything. I’m just floating, and feel rather dopey. I’m used to being in control.

#2 I love it ! ! ! ! I don’t have a care in the world. All my troubles are a million miles away as I just float along.

Love it or hate it, both groups are describing the same feeling. Neuropharmacology can help to tell us why opiates produce this feeling, but it can’t tell us why some like it (about 5%) and the majority (95%) do not. This clearly is the province of psychology and psychiatry. It’s the Cartesian dualism between flesh (opiate receptor) and spirit (whether you like what it does). It also shows the limitation of purely physical reductionism of the way we react to physical events.

The phenomenon of a small percentage of people becoming addicted to a mind altering substance is general and is not confined to one class of drug. We were told never to prescribe chronic benzodiazepines (valium, etc. etc.) to a recovered alcoholic. People who get hooked on one thing are very likely to get hooked on another.

I realize that some of this could be criticized as blaming the victim, but so be it. Medical facts are just that, like what they say or not.

Addendum 11 Sep ’16 — I’m not saying that you won’t become physically dependent on opiates if you get them long enough and at high enough doses. We all would. Even if this happened to you. When you no longer needed them for pain and went through medically supervised withdrawal, you wouldn’t crave them, and do crazy things to get them (e.g. you were physically dependent but never addicted to them — it is important to make the distinction).

Example — when I was in the service ’68 – ’70, we had half a million men in Vietnam. Everyone I’ve talked to who was over there says that heroin use among the troops was 25 – 50% (high grade stuff from Thailand was readily available). As soon as they got back to the states, the vast majority gave them up (and with minimal withdrawal requiring my attention – I think I saw one convulsion due to withdrawal).

A non-addicting painkiller?

Synthetic organic chemists, molecular modelers and X-ray crystallographers fire up your engines. A great target is available, discovered by the humble centipede of all things.

Several times during my career as a neurologist, a new drug was ballyhoo’d as a non-addicting narcotic — Talwin springs to mind, among others. The hope was that a molecule with both agonist and antagonist properties wouldn’t be addicting. All basically inhibited neurotransmitter release (like the opiates), to which the synapse responded by making more receptors for the neurotransmitter, explaining tolerance, addiction to the new drug and why junkies can take doses of morphine that would kill you and I.

Have a look at Proc. Natl. Acad. Sci. vol. 110 pp. 17534 – 17539 ’13. Here’s some background. To conduct a nerve impulse, neurons have to let sodium ions flow through their membranes. This is done through proteins called sodium channels. We have 9 distinct genes for them, and most neurons express more than one.

Consider the humble pufferfish. It sometimes makes a beautiful organic molecule called tetrodotoxin (http://en.wikipedia.org/wiki/Tetrodotoxin) which blocks all but 2 of our sodium channels stopping them from conducing sodium ions. It can kill you and is 100x more potent than cyanide. Even so, it’s a very pretty molecule (to an organic chemist) with some resemblance to adamantane.

The centipede makes a 42 amino acid protein which essentially blocks only one sodium channel (NaV1.7). It’s quite potent, doing this at a concentration of 25 nanoMolar. Clinically, it is even more potent than morphine (well, in animal models anyway)

So why get excited? Because as far as we can tell, its action is on peripheral nerve fibers, not the brain. For some reason nerve fibers carrying painful impulses (a philosophic conundrum — impulses themselves are no more painful than a fire feels hot to itself) from the periphery to the spinal cord and brain use lots NaV1.7. So addiction shouldn’t be a problem.

There were some clues already — there is a disorder called congenital insensitivity to pain [Nature vol. 444 pp. 831 – 832 ’06], due to loss of function mutations in NaV1.7. Other mutations here cause several painful syndromes — erythromelalgia [J. Med. Genet. vol. 41 pp. 171 – 174 ’04 ], chronic rectal pain. These mutations cause a hyper functioning sodium channel which stays open too much.

Total absence of pain isn’t good, as we need it to warn us that we’re stressing our joints excessively. In the bad old days when there was a lot of syphilis around, it sometimes caused peripheral nerve degeneration, resulting in something called Charcot joints — http://en.wikipedia.org/wiki/Neuropathic_arthropathy.

So get cracking guys, if tetrodotoxin, a small compact molecule can nonspecifically block most sodium channels, surely you should be able to find something smaller a 42 amino acid protein to block NaV1.7 (selectively of course). I’m not sure that we have a structure of NaV1.7, but others are known, along with all their amino acid sequences, so it should be possible to model binding sites by analogy.