Dear Frederik,

Many years ago I wrote a paper in "Opioids and Pain". I described as below:

Electrophysiological studies have reported both presynaptic (indirect) and postsynaptic (direct) facilitatory and inhibitory actions of opioids on synaptic transmission from many regions of the nervous system. Direct inhibitory effects of opioids are mediated by opioid receptors coupled to pertussis toxin-sensitive Gi/Go proteins, and direct excitatory effects via a cholera toxin-sensitive Gs-like protein (Crain & Shen 1990;Cox 1993; Johnson et al. 1994). For details and references see my paper below.

best wishes,

Refik

Article Opioids and pain

Dear Refik,

Thank you very much indeed for your promt reply to my question. I will read your paper with much interest.

Kind regards,

Frederik de Wolff 

Hallo Fre, I know from clinical experience that indeed some children react being excited and can't sleep. It was known 50 years ago since Prof. Sam van Creveld teached me about it and warned to be careful. But I can't really help you, as ever Janna Koppe

Freek, kijk eens in de opiaat receptor distribution in het brein. Heb het niet bij de hand, maar dacht iets als opiaat receptoren in de agressie gebieden. Hou me er niet aan, kan het mis hebben. Enrico

Thanks Janna. This phenomenon was taught to me in Leiden more than 50 years ago by Prof. Erik Noach. Apparently it was well known by then, but apart from clinical experience I've never come across its incidence and mechanism. All the best, Freek

Thanks, too, to Enrico. Yes, it could be a matter of receptor distribution but also a structural abnormality. Best wishes, Freek

I have no suggestions as to the mechanism but the sedative effect of stimulants in hyperactivity syndromes and the stimulant effects of barbiturates in another group were investigated decades ago by H J Eysenck and I think he related it to some aspects of the personality types in his Eysenck Personality Inventory but it was a long time ago and I don't recall the details. Paradoxical effects are not rare with opiates and may be particularly common with tramadol, though it is not a typical agonist. I read somewhere that it was one of the most sought-after items smuggled into Gaza because of its energising properties. In a chapter about prohibition[1] I cited the journalist Michael Davidson who "reported that when in China, someone ‘took me to see his friend Mr Wu, who kindly helped me to make my first, and last, attempt to enjoy opium. Mr Wu was an author...But he was able to compose only after several pipes; he would smoke during the later hours of the day and devote the night to writing’."

[1] Brewer C. SOCIAL AND ECONOMIC BENEFITS OF ENDING THE ‘WAR ON DRUGS’. In: Health Capital and Sustainable Socio-economic Development (Ed; M Motlagh) Taylor & Francis. 2008 

Paradoxical effects are not uncommon with many substances, (thanks Colin for mentioning the paradoxical effect of stimulants in patients diagnosed with ADHD; this is a great example). Different people metabolise drugs in different ways, and everyone’s nervous system is in some ways unique. For example, SNPs (single-nucleotide polymorphisms) in genes that code for neurotransmitters or their receptors and transporter proteins can lead to the person who carries that mutation responding very differently to any drug that interacts with those neurotransmitters and/or the neural structures they engage with. Different people may be affected by the same drug in quite different ways. For example, this SNP has been associated with different responses to pain, and with different outcomes in treatment for opioid dependence;

http://www.snpedia.com/index.php/Rs1799971

Here’s a recent meta-study on SNPs opioids and pain response;

http://www.ncbi.nlm.nih.gov/pubmed/25794200

One of my colleagues is a “complete opioid non-responder” which means opioid drugs do not provide her with any pain relief, although they do still make her nauseous and cause emesis in high doses; (non-responders to morphine or other specific opioids are not that uncommon, but non-response to all opioids is very rare). A few years ago she needed to have a hip replacement, and her anaesthesia during the surgery and post-operative pain-management had to be managed with ketamine and other non-opioid drugs.

The term “paradoxical response” is in my opinion used a little loosely in the medical literature, as it is applied to cases where someone naïve to a substance responds in an abnormal or unexpected way to a therapeutic dose of that substance, but it is also applied to cases where someone is prescribed a drug chronically and then develops unusual responses. In the first case the response is analogous to an allergy; the patient naturally reacts to the drug in the opposite way we would expect. In the second case the unusual response is due to neuroadaption to the substance. For example, opioid-induced hyperalgesia (increased sensitivity to pain) is described as a paradoxical reaction to opioids, however in most cases so diagnosed it might better be understood as a function of tolerance to chronic use of opioids.

In the past I have worked with two benzodiazepine-naïve patients who had paradoxical responses to benzodiazepines. Both of these patients became excited and talkative, then physically agitated, restless and anxious when given even modest doses of valium. (Oddly enough, they both had paradoxical responses to diazepam, but not to other benzodiazepines, and so the problem was easily resolved by prescribing a different drug). These two cases would fall into the first category of paradoxical response I have listed above.

http://www.ncbi.nlm.nih.gov/pubmed/15460178

However the literature is also full of case-histories of people prescribed benzodiazepines for prolonged periods of time who then develop paradoxical responses, (such as disinhibition, aggression, retrograde amnesia, automatic behaviours and behaviour considered highly atypical for the patient) and these are almost always associated with the patient becoming habituated to high doses of the benzo involved, so that they no longer fall asleep, even if they are in a dream-like state when the bizarre behaviour occurs. I have met many normally law abiding people who (for example) went on a shop-lifting spree or committed other antisocial criminal acts whilst heavily intoxicated with benzodiazepines, only to wake up with no memory of the incidents at all. This is not akin to an “allergy”; rather it is an acquired tolerance to some of the drug’s effects but not to others.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1672080/pdf/brmedj01431-0052a.pdf

https://www.ncbi.nlm.nih.gov/pubmed/22059213

So, to return to opioids; in the case Colin cited of "his friend Mr Wu", (who reportedly would smoke opium and then write creatively all night), this may be a paradoxical effect of the first category, but I think it might be more accurately described as a normal result of habituation and dependence.

Not everyone who uses opioids in a non-medical fashion is doing so in an attempt to sedate themselves into oblivion. There are many cases of functional users of heroin, morphine, and other opioids, including some highly regarded medicos;

(eg see https://en.wikipedia.org/wiki/William_Stewart_Halsted )

When someone is habituated to a regular and consistent daily regime of functional doses of opioids, they typically do not appear intoxicated or sedated at all. Typically they appear calm, focused and are capable of sustained attention for unusually long periods of time. Prolonged physical activity also appears easier. In traditional opium growing regions of South East Asia farmers traditionally smoke small amounts of opium each morning before labouring in the fields tirelessly all day.

If Mr Wu was accustomed to using a consistent dose of opium each evening, it is not paradoxical for him to have then spent the night writing; he would have felt comfortable and relaxed physically and mentally. However on any night when he didn’t consume opium he would probably have found it extremely difficult to focus on his writing…

I didn't mean to pin too much on Mr Wu but it occurs to me that if he only took a short-acting drug like morphine for an hour or two once a day, he may not have been physically dependent. Heavy drinkers who only drink in the evening may not be physically dependent either. As interesting as the phenomenon of paradoxical reactions is the clinical and research finding that the intensity and duration of withdrawal symptoms bear little relationship to opiate dose and I wonder if this is sometimes related to paradoxical mood responses. I recall a tough paratrooper who had very distressing symptoms during withdrawal from only 2mg of buprenorphine and other patients who had mild symptoms and recovered quickly despite taking several grams of heroin or three-figure doses of methadone daily.

Hi Colin,

I have had personal experience, at different periods in my life, of non-medical dependence upon opium, morphine, and heroin. In my current work role I've also had the opportunity to observe large numbers of people experiencing dependent non-medical use of various opioids (amongst other substances).

Based on my experience I believe you are quite correct Colin- while the dose, pattern of use, and duration of use are all to some extent predictive of severity and duration of withdrawal symptoms, the dose alone is not necessarily a good indicator. My own, personal experience of heroin dependency over several years was that each time I withdrew the withdrawal symptoms were worse but also persisted for a longer period of time, The last time I withdrew "cold turkey" from a heroin habit I had been abstinent for almost two years before relapsing, had only been using the drug for a period of

I am interested in the polymorphisms that exist for instance in the use of paroxetine, is any body aware of thsee polymorphisms?? Espacially those related tomthe function of bone and trombocytes? thanks, Janna 

Hi Janna,

Cytochrome P450 2D6 is the enzyme that metabolises paroxetine (and a lot of other medications as well, including opioids).

CYP2D6 is the gene that codes for this enzyme, and there are more than 20 variant alleles. Patients show normal, decreased, or no CYP2D6 function, depending on the allele. Depending on the individual's genetics, they may metabolise a drug more quickly than 'normal", normally, more slowly than normal, or not at all...

If you are a "non-metaboliser" or a "slow metaboliser", you will receive less benefit from any drugs that this enzyme breaks down into more active substances (eg codeine is a "prodrug", which means codeine does pretty much nothing, until CYP450 2D6 converts it to morphine inside your liver. If you are a non- or slow-metaboliser, codeine will provide little or no pain relief).

Conversely, is you are a non- or slow-metaboliser of a drug that your liver breaks down into a weaker or inactive metabolite,  then you will receive more of the drug effect for longer than someone who is a "normal"-metaboliser (and a "fast-metaboliser" will receive less effect and find the drug wears off faster).

If you are a "non- or slow-metaboliser" of paroxotine, the chances of toxicity are greatly increased for this reason. What's more, paroxotine inhibits CYP2D6 function, (as do fluoxetine (Prozac), citalopram (Celexa), and a number of other medications). This is a 'double whammy'.

There's a list of inhibitors (and inducers) here;

https://en.wikipedia.org/wiki/CYP2D6#Ligands

There are pharmacogenomic test kits available which can identify if you are a "slow", "normal" or "fast" metaboliser.

Non-responders to opioids, and CYP450 2D6;

http://www.practicalpainmanagement.com/treatments/pharmacological/opioids/non-responsive-pain-patients-cyp-2d6-defect

Good overview of SSRIs and CYP2D6;

http://emedicine.medscape.com/article/1879354-overview

Hope this is useful?

Regards,

Paul.

In simple terms it is called as hallucination.

G'day Jai,

Hallucinations are a possible but reasonably uncommon adverse side-effect of medical treatment with opioids.

This is a result of toxicity rather than a true 'paradoxical' effect. As many of these cases involve elderly patients, it is often difficult to differentiate between opioid-induced hallucination and symptoms of dementia and age-related cognitive decline.

There's a typical case history here;

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804023/

.

When people require opioid therapy but begin developing adverse side-effects, (typically nausea, constipation, or pruritus), rotation (ie switching to a dose-equivalent regime of a different opioid) will usually resolve the symptoms.

See;

http://www.aafp.org/afp/2006/1015/p1347.html

.

Regards,

Paul.

Dear Paul thank you so much for your comments on cytochrome P450 2D6 and paroxetine. I am so interested because I am trying to explain the problems in 2 boys, severely brain damaged by subdural haemorrhages and maybe hypoglycaemia. They were born both in face presentations instead of the occiput, the mother used 20 mg paroxetin a day in pregnancy. I think the abnormal position of the children might be related to a lower muscle tone, since the pelvis of the mother is normal ,  she had 2 children in occiput position before, when not using paroxetin. These last 2 children also developed severe subdural haemorrhages and are brain damaged.  Unfortunately no blood Sugar is measured after birth. So part of the brain damage can also be related to hypoglycaemia. I wonder if there was a bleeding tendency in these two children at least an abnormal function of the blood platelets in combination with abnormal bone development, both are described as related to paroxetin. Thanks very much, Janna

Frederik A De Wolff 45.02  Leiden University

What is the incidence and mechanism of the excitatory effect of opiates in some humans?

Some patients on opiate or opioid analgesics paradoxically react with hyperactivity, verbosity and insomnia. As a student (more than 50 years ago) this was demonstrated during the pharmacology lectures bij injecting a cat with morphine and show it a white mouse, whereupon the cat panicked and jumped up and down its cage. Our pharmacology professor then explained that 'a small percentage of the human population reacted like cats', and indeed, this is reported incidentally by patients.

Can anybody explain the incidence and mechanism of this paradoxical effect?

What is the incidence and mechanism of the excitatory effect of opiates in some humans?. Available from: https://www.researchgate.net/post/What_is_the_incidence_and_mechanism_of_the_excitatory_effect_of_opiates_in_some_humans [accessed Jun 6, 2017].

 Charles Schaffer & I found evidence that nearly one-third of bipolar patients when taking mu-opiates would have a manic-like reaction that might last a day or two.  In some cases this was the subject[s first manic episode.  There is evidence of interaction between dopamine and opiate system and perhaps a large subset of bipolar patients might be overly sensitive to the DA-opiate interaction.  We published one report but not the second, which had incidence around 35 percent.  Thanks you.Tom Nordahl UCD

Thank you so much Tom for this very interesting and relevant contribution to this discussion. I had the impression that also in non-bipolar patients with chronic pain the occurrence of this paradoxical effect is much higher than just incidental.

Thanks again, Frederik de Wolff, Leiden University Medical Centre

Academic veterinarians have pointed out to me that the use of mu-opiates for pain in animals, such as cats & dogs, can induce excitatory/hyper-active responses.