live, love, hurt

A long-experienced phenomenon, tolerance is the need to increase the dosage of medication to achieve the same effect. This is most frequently seen in illicit drug abuse. Heroin users quickly have a need to take increasing doses in order to achieve the same “high.” The same goes for other illicit drugs like amphetamines and cocaine. With most drugs tolerance is a complicated process and is not fully understood. In most cases we assume the neurotransmitters (or their receptors) affected by the specific drug type is down-regulated in some way. That is to say, if you take a lot of opioid analgesics your body reduces the amount of naturally-produced (endogenous) opioids, and also decreases the amount of opioid receptors in the body.

Some time ago, it was noticed that NMDA receptor antagonists (dissociative anesthetics) like ketamine, phencyclidine, and dextromethorphan have the side-effect of reducing the amount of tolerance formed to opioid analgesics. This has far-reaching implications because if you can mediate opioid tolerance, you can control the amount of opioid needed for pain relief.

The NMDA receptor both induces and maintains persistent enhancements of the excitability of neurons to prolonged stimulation, or “wind-up.” Wind-up is a key spinal mechanism requiring activation of the NMDA receptor that both amplifies and prolongs certain types of pain. As a result, wind-up may be one of the events underlying prolonged or chronic pain. Evidence from animal studies indicates that this mechanism is involved in the induction and maintenance of certain types of pain, most notably inflammatory and neuropathic.

Neuropathic pains are at least partly mediated by the NMDA receptor, which may relate to changes in opioid sensitivity. All opioids reduce, or with high doses block the input that causes certain types of pain, probably via activation of the presynaptic opioid receptors to prevent the release of primary afferent transmitters and so prevent pain input from actually activating the neurons that make you feel pain. However, if the pain continues, wind-up overcomes the inhibitions of input and the neurons commence firing, causing pain. As wind-up increases the activity of neurons, a higher dose of opioid will be required to block the increased excitability. Thus, at moderate doses, opioids delay wind-up without inhibiting the process itself. In contrast, NMDA antagonists abolish wind-up. Thus, threshold doses of morphine combined with low doses of NMDA antagonists are able to elicit dramatic inhibitory effects, a synergism that suggests low probability of side effects. Importantly, in a model of neuropathic pain where morphine is inoperative, the co-application of an NMDA antagonist restored the ability of morphine to inhibit the response.

All that medical speak translates to this: the pain input that’s prolonged and intensified by NMDA receptors can be delayed by opioids, but not inhibited. However, NMDA antagonists (mentioned above) completely turn off the prolongation and intensification, allowing opioids to take away that pain. Basically stated, it amounts to the aforementioned. Adding a mild NMDA receptor antagonist (in extremely sub-anesthetic doses) to an opioid enhances the effects of the opioid, allowing smaller amounts of opioid, and thus fewer side-effects.

At least there’s one good use for dextromethorphan.

Memorial Day almost killed me.

I awoke under an avalanche of pain, grasping in vain for the bottle usually kept on the floor by my bed. This bottle normally holds little pills of doctor-sanctioned relief, but not that day. The refill date was more than a week away, but I’d already run through my monthly allotment.

I had a bad couple of weeks, so I took more pills than I’m prescribed. A lot more. What am I supposed to do, suffer, even though I have pills that will ward it off? Will doctors ever understand this simple situation? I’m in pain, and it’s not being properly managed. If you were miserable, you’d take the pills too. If it were your wife suffering, she’d take the pills too. I’m not allowed to, because I’m just a chronic pain patient.

Three or so years ago, my lower back started hurting occasionally. I took ibuprofen and brushed it off. A year later, I’d taken so much ibuprofen my stomach couldn’t digest my own fluids anymore. I had no health insurance. It got so bad I finally went to an emergency room one night, and they gave me Flexeril (cyclobenzaprine), Naprosyn (naproxen), and Tylenol #3 (co-codamol 30-325). The Tylenol #3 was glorious for a short week. I could work again and not want to die because of it. I followed up at a free clinic, where the doctor claimed he couldn’t help me, and wouldn’t provide me with medicine. I suffered more, and went to the ER time after time. Occasionally I’d get a shot in the rear and a couple days worth of pills, but usually I was kicked out under suspicion of drug-seeking.

I’d never done drugs.

I moved across the country to get a good job with health insurance, so that I could see doctors who might care. I went through an orthopedist, rheumatologist, a gastroenteroligst, and a cardiologist; I’ve had three failed facet joint injections, two MRIs, more x-rays than I can remember; and, ultimately, was still no closer to an answer. I finally started seeing a board-certified interventional pain management doctor. He put me on Lortab 10 (hydrocodone-10, acetaminophen-500) every six hours. I was so, so very happy to not spend every moment of every day curled up in a ball waiting, hoping, to die. He did some interventional therapy such as nerve blocks, yoga, and was convinced it was my facet joints. Then he was convinced it wasn’t my facet joints. He threw some prednisone and Valium (diazepam) at me, and told me to do an epidural.

He only allows one pill every six hours, but they last two at best. My pain is not managed properly, and I still spend a significant amount of time in a significant amount of pain. So when I have bad weeks and end up taking more than one pill every six hours I’m threatened that he won’t treat me anymore. I’ve been through 10 doctors, three years, a million tests, and I’m still drug-seeking? Please, I live in Baltimore. I could go down to the corner and score an 8-ball far easier than I could get a doctor to prescribe me relief. Cheaper, even. Some days I even consider it, in a dark corner of my mind. Pain will drive you to think and even do things you’d never normally do. No one truly understands pain until you’ve lived with it every second of every day for years.

I dug through the closet, looking desperately for a bottle I may have forgotten about. I dug through couch cushions and checked behind my desk. I looked under the kitchen table and tore my bed apart searching in vain to find a misplaced pill. I took my old, empty bottles and filled them with water to capture any residue left by the pills and drank it down in hideous gulps. I tried calling my doctor, but of course they were closed. I left voicemails. Suddenly, I remembered I’d been calling them for days, trying desperately to get an extension, so I checked my voicemail to find my pain doctor called in some extra medicine to my pharmacy. I was saved. I wouldn’t have to suffer through this. I dashed to the car and sped to the pharmacy. I walked up and tugged on the door only to discover it was locked. I stood back for a moment, then tugged again. Still locked. A sign on the door read “Closed for Memorial Day.”

I stood there for a while before climbing back into my car and staring off into space for ten minutes, tossing illegalities around in my head before accepting my eventuality. I drove home and called off work. I made some tea, got a trash can, and prepared for the wonder that is opioid withdrawal. Twelve hours after my last dose I started to feel shaky, nervous, uncomfortable, and generally terrible. Then the nausea came. I laid at the end of my bed, my head hanging off the edge, staring into the trash can. My bowels started to rumble so loudly I thought it was storming outside, and I made a mad dash for the bathroom with fluids coming out of both ends at once. The rest of my day was spent in the bathroom, puking and shitting my way through the night. It was in full swing now, and I was shaking, cold yet sweating. I had waves of the opposite of pleasure rushing through my body that pushed every last scrap of material out of my stomach and bowels. My eyes were puffy and red; my pupils dilated to the size of dimes. I sweat almost as much as I puked. I couldn’t feel my legs, so I crawled. I crawled around with one eye closed because of double vision so drastic I couldn’t locate the toilet. If I moved my head too quickly my vision would break up into frames, as if I were watching reality on a 35mm projector that wasn’t quite up to speed. I looked like a heroin addict that couldn’t get a fix. My normal back pain was amplified six, eight, ten times. I realized this must have been the definition of hell.

This went on for eight, nine, ten hours before the vomiting and diarrhea subsided and I crawled into bed, shaking, unable to do anything but pray for the day to end. The next morning I awoke in a miserable torrent of pain. I couldn’t think straight, I didn’t feel right. I felt like reality was now different, and my brain was permanently stuck this way. I pulled my miserable heap of a body out of the sweat-soaked pad of a bed and threw myself into a tub of hot water. I soaked for an hour before I managed to sloth out of that and make myself look enough unlike a junkie to drive to the pharmacy and pick up my medication. Within 30 minutes I was back to feeling my own tortured version of normal. The pain was lessened, but present. The major benefit was no longer feeling like a giant pile of walking vomit.

Why is this my life? Why don’t pain doctors understand that their patients are in, you know, pain? I’ve told him a dozen times the pills aren’t enough, and the answer is always “keep taking them anyway.” I’m miserable. My life is a joke. Every second of every day is a painstaking journey through an illustration of the failure of the United States healthcare system. Every test is normal every time. Every treatment fails to provide pain relief or any clue as to the origin of the pain. Why am I 22 and in chronic pain with no trauma? Why does everyone dismiss rheumatological diseases when they fit the best? I didn’t hurt my back, my back hurt me.

So now I’m suffering constantly and dependent on painkillers to even get through the day. I am not an addict. Withdrawal and dependency do not imply addiction. I’m just a minority. I’m just a lowly chronic pain patient, who has abandoned all hope.