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Analgesics - opioids [pharmaceuticals]

Category: Medicines

Type

Involuntary

Introduction and description

 

There are various sorts of drugs used in pain relief.  The section on pain killers and NSAIDs describes one type of pain killer, but there is a class based on opiumCodeine and morphine are two important pharmaceuticals within this class of drugs and are described separately, but this section deals with opioids.

Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to the natural alkaloids found in the resin of the opium poppy. 

Opiates are among the world's oldest known drugs. The analgesic (painkiller) effects of opiates are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance.  But the effects of opioids is less certain.  Opiates are natural substances, opioids are pharmaceutically manufactured substances and their effects are sometimes very different.

 

The side effects of opioids can include sedation, respiratory depression, constipation, and depression. Opioids can also cause cough suppression, so they are used in cough medicine, although this may not be obvious on the bottle you buy from the chemist.

They are all extremely addictive and can lead to appalling withdrawal symptoms after continuous use or high use followed by abrupt discontinuation.

The following is appalling, at least I was appalled.   It appears that in some countries these pharmaceuticals are used on babies.

Fentanyl is a synthetic opioid that is very important in anaesthetic practice because of its relatively short time to peak analgesic effect and the rapid termination of action after small bolus doses. The objective of this survey is to review the clinical pharmacology of fentanyl in preterm infants. The bibliographic search was performed using PubMed and EMBASE databases as search engines. ….In neonates, fentanyl half-life ranges from 317 minutes to 1266 minutes and in adults it is 222 minutes. Respiratory depression occurs when fentanyl doses are >5 μg/kg. Chest wall rigidity may occur in neonates and occasionally is associated with laryngospasm. Tolerance to fentanyl may develop after prolonged use of this drug. Significant withdrawal symptoms have been reported in infants treated with continuous infusion for 5 days or longer. Fentanyl is an extremely potent analgesic and is the opioid analgesic most frequently used in the neonatal intensive care unit.  PMID:  25176283

In the extract which follows all these drugs are opioids.

World Health Organisation; Technical Report series no 188 - Expert committee on addiction producing drugs
The WHO cited the following drugs as being particularly noteworthy because of their high addictive potential coupled with dangerous side effects – principally respiratory depression;

  • Allylprodine
  • Benzethidine is related to pethidine (meperidine).
  • Furethidine is also related to pethidine. 
  • Metazocine is related to pentazocine.
  • Pentazocine 
  • Phenazocine  - see Pentazocine
  • Piminodine (Alvodine) is an analogue of pethidine

The Drugs

There are four main opioid receptors. The delta and mu  receptors provide pain relief.  The kappa receptor was once thought to, but it is looking increasingly likely that it may not. 

Pharmacological studies and recent research using genetic approaches have indicated that most actions of exogenous opioids, such as morphine, are mediated through the mu-opioid receptor. By contrast, the function of the kappa-opioid receptor in opioid actions largely remains unclear. In this article, we discuss the accumulating evidence that activation of the kappa-receptor antagonizes various mu-receptor-mediated actions in the brain, including analgesia, tolerance, reward and memory processes. The neural mechanism for this potentially ubiquitous mu-opposing function of the kappa-receptor is believed to involve distinct locations of the two opioid receptors on physiologically different cell types in local neuronal networks that are implicated in an opioid action.  PMID:  9584625

For more details see Opioid receptors. 

 

It is thus possible to argue that the mu/delta combination is the best one for clinical treatment,  simply on the basis that the mu/delta receptors provide relief from pain, whereas the kappa receptor doesn't and produces appalling side effects.  Opium is principally a mu/delta product although its action is subtle. 

The majority of the pharmaceuticals have extremely strong kappa action.  The theory is that by having strong kappa action, they will not be so addictive, since the euphoria, bliss and feel good effects assocated with the mu and delta receptors are not present.  But to get any pain relief, at least some mu and delta action has to be present, as such there is an argument that says, they could be more addictive, since the person craves bigger doses to get the euphoria and counteract the dysphoria.  The table below summarises the activity of each receptor: 

Delta and mu

Kappa

Provide pain relief

 

Antidepressant effects

 

Sedation, relaxation

 

Euphoria pleasure

 

Constipation

 

Hypothermia

 

Itching

 

Constriction of the pupil

 

Respiratory depression

 

Negligible, or more likely, no pain relief

Respiratory depression

Sedation

Dysphoria

Nausea  and vomiting 

Cardiovascular

Visual distortions

Sexual depression and impotence

Hair thinning

Learning and memory an inability to remember human faces, or names and a lack of social skills and the ability to work with social cues

Discontent,  anxiety, insecurity, ‘jitteriness’

Inability to love or bond or even care about anybody

Suspiciousness, paranoia, control freakery, fear, distrust, meannesss, stinginess

Lack of empathy

Diuretic

 

 

Opioid pain medications ... are commonly prescribed to patients for chronic non-cancer pain. However, little evidence exists for their effectiveness in most pain states, including chronic pelvic pain. Whenever possible, initiation of opioid pain medications in chronic non-cancer pain should be avoided. If patients present for evaluation of disease states ....already using regular narcotics, physicians should be aware of ways to mediate misuse and diversion.   PMID:  25155127

This paper also goes into some detail about the need to find out the CAUSE of the pain.  As a form of temporary relief until the cause is found - assuming one uses a medication with high mu and delta activity - opiates [not opioids] may have a place, but as this paper points out, the objective should be to find out why there is pain and to treat this, not to suppress the pain.  Pain is an indicator that something serious is wrong, and as such to suppress it, simply allows whatever the real problem is to become worse, until it eventually kills you.

See Healing yourself.

 
 
 

This rather begs the question – why are there so many hundreds upon hundreds of products on the market from pharmaceutical companies that appear to target the ‘wrong’ receptors – many of them perfectly legal and many of them prescribed to quite vulnerable people? 

And of course the answer is money.   

 

 

 

 

 

Interestingly, the potential for money making is more than one would at first imagine.  Opioids provide little real pain relief, as such people take and ask for more and more of them from their doctor, but the drugs produce dysphoria - the opposite of euphoria, in effect they cause stress and depression.  So, a person on pain killers will suffer from depression, go to their doctor and be put on anti-depressants, so from a drug company's point of view as long as they sell both they are onto a real  income earner.

 

Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a kappa-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. ….. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria.  PMID:  18184783

So, stress, depression, anxiety and all the other negative emotions that are the opposite of bliss are mediated through the kappa receptor.  In nature it has a natural balancing function, but we are playing with receptors when we use opioids.

The results suggest that stress-induced drug craving may require activation of the dynorphin/kappa opioid system. PMID: 18575850

In effect, feed anyone opioids and you are almost guaranteed to turn them into a drug addict - legal or illegal.

Side-effects

The table above provides the side effects experienced on a general level when using these products.

 

One additional side-effect, which is getting more attention these days because it is a growing problem, is death. 

Because of the addictive nature of all these drugs, it is not uncommon to overdose. 

In effect, a person, desperate to get the small amount of euphoric mu/delta effect these drugs produce, takes more and more. 

But there is a far greater effect on the receptors that produce respiratory depression, cardiological problems, dysphoria, and so on, and as a consequence they die from heart failure, or the equivalent of asphyxiation.

How it works

I will now quote a PubMed paper which should explain why people get hallucinations, out of body or visionary experiences from opioids, although the explanation is essentially mechanistic as opposed to functional.  It may be worth adding that dysphoria is despondency of a level you cannot imagine without having been there – so low you are in an abyss of unfathomable horror.  Thus the corresponding hallucinations may well be of hell.

KOR agonists also produce side effects such as dysphoria and hallucinations, which limits their clinical usefulness.  It has long been understood that KOR agonists are dysphoric.  It is now widely accepted that KOR agonists have dissociative and hallucinogenic effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs. It is believed that the hallucinogenic effects of drugs such as butorphanol, nalbuphine, and pentazocine serve to limit their opioid abuse potential, however, in the case of salvinorin A, a structurally novel neoclerodane diterpene KOR agonist, these hallucinogenic effects are sought after, even though the experience is often considered dysphoric by the user. The involvement of the KOR in stress, as well as in consequences of chronic stress such as depression, anxiety, anhedonia, and increased drug-seeking behaviour, has been elucidated.


Note that there is also a point where if the amount is at overdose proportions the effects may actually be being obtained because we are being poisoned  - see poisoning

What is happening then is that the body finds itself being bombarded by a chemical it feels it doesn’t need at very high levels and is then treated as a threat to which the body needs to respond.  The itching shown in the list above as a side effect  is probably a result of over stimulation of the immune system and the release of an excess of histamine.

References and further reading

  • Obstet Gynecol Clin North Am. 2014 Sep;41(3):491-501. doi: 10.1016/j.ogc.2014.04.005. Epub 2014 Jul 2.  Opioid Use and Depression in Chronic Pelvic Pain.  Steele A.  Obstetrics, Gynecology and Women's Health, Surgery, Saint Louis University, 6420 Clayton Road, St Louis, MO 63117, USA. Electronic address: steeleac@slu.edu.
  • J Neurosci. 2008 Jan 9;28(2):407-14. doi: 10.1523/JNEUROSCI.4458-07.2008.  The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system.  Land BB1, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C.  Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
  • Trends Pharmacol Sci. 1998 Mar;19(3):94-8.  mu-Opposing actions of the kappa-opioid receptor.  Pan ZZ.  Department of Neurology, University of California, San Francisco 94143, USA.
  • Psychopharmacology (Berl). 2008 Sep;200(1):59-70. doi: 10.1007/s00213-008-1122-y. Epub 2008 Jun 25.  Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system.  Redila VA1, Chavkin C.  Department of Pharmacology, University of Washington, 1959 NE Pacific St., Seattle, WA 98185-7280, USA

Observations

The figures below are from eHealthme and were correct as at 2012.  The numbers have since grown considerably and the observations themselves provide an updated view.  We will not be continually updating these figures.  The links to the eHealthme site that we provide can be used for up-to-date figures, our objective is simply to get a feel for the number of hallucinations that are resulting.

The number of hallucinations come from doctor submitted Adverse Drug Reports submitted to SEDA and the FDA figures and then summarised for the eHealthme web site.  A link has been provided from each drug to the eHealthme site.  If this no longer works, it may mean the drug has been withdrawn, or that eHealthme have reorganised the site.  The link to the eHealthme site can, however, still be used to do a search using the drug name.

Elvis Presley

Elvis Presley was a heavy user of Demerol.  His death is reputed to be from use of the drug and also has been blamed on his decline as a singer.  He originally took it as a pain killer and then became addicted, rationalising as many do that it was ‘only a pain killer’ and was prescribed by his doctor 'who must know best'.  The pain was from the hurt of a broken marriage, it was emotional pain, not physical pain.  His rival was called Stone and he said once

"’There's too much pain in me ... Stone [must] die’. His outbursts continued with such intensity that a physician was unable to calm him, despite administering large doses of medication”. 

Demerol, Pethidine or meperidine is a once popular synthetic opioid analgesic ….  For much of the 20th century, pethidine was the opioid of choice for many physicians; in 1975 60% of doctors prescribed it for acute pain and 22% for chronic severe pain……

 

Compared with morphine, pethidine was thought to be safer, carry a lower risk of addiction and to be superior in treating the pain associated with biliary spasm or renal colic ….. It was later discovered that these were all myths and that it carried an at least equal risk of addiction, possessed no advantageous effects on biliary spasm or renal colic compared to other opioids and that, due to its toxic metabolite, norpethidine, it was more toxic than other opioids, especially during long-term use. It was also discovered that the norpethidine metabolite had serotonergic effects which means that pethidine could, unlike most opioids, contribute to serotonin syndrome.

So there you are, death by doctor.

Observation identifiers

Observation name

No of hallucinations

0002762

The road went on and on

1

003662

Darvocet

96

003663

Fentanyl and fentanyl analogues

0

 

Fentanyl

416

 

Duragesic

144

 

Actiq

41

 

Fentora

16

003664

Morphine analogues and derivatives

0

 

[Morphine

397]

 

MS Contin

226

 

Avinza

228

 

Kadian

227

 

Oramorph

77

 

Dilaudid

37

 

Palladone

36

003665

Pentazocine and derivatives

0

 

Talwin

1

003666

Pethidine and pethidine analogues or derivatives

0

 

Meperidine

5

 

Demerol

31

003667

Tramadol and related drugs

0

 

Tramadol

231

 

Tramadol

80

 

Tramadol hydrochloride (biovail)

139

 

Ryzolt

138

 

Ultram

221

 

Ultracet

10

 

Tapentadol

3

 

Nucynta

2

003668

James Cracknell and Ben Fogle

1

003669

Buprenorphine

0

 

Buprenorphine   

21

 

Suboxone Buprenorphine

25

 

Subutex

27

 

Suboxone

25

003670

Hydrocodone

0

 

Hydrocodone or  dihydrocodeinone

131

 

Vicodin and  Vicodin ES

222

 

Norco

220

 

Hycodan (or generically Hydromet)

5

 

Hycomine

1

 

Lorcet

16

 

Lortab

328

 

Norco

220

003671

Oxycodone

0

 

Oxycodone and  Oxycodone

229

 

Roxicodone

229

 

Oxycontin

226

 

Percocet

154

 

Roxicet

63

003672

Oxymorphone

0

 

Opana

6

 

TOTAL

4,952

A list of the other drugs in this class for which no observations could be found are in the science section Opioid analgesics other drugs

Deaths

We also have a list of the deaths attributed to Opioid analgesics in the science section, please follow this link.  The figures come from eHealthme and thus are derived from doctor submitted Adverse Drug Reports.  The total deaths from all the drugs listed above in the chart, as at the end of 2016 and applicable only to the USA was

17,044

 

Related observations