Some History

Humans discovered opioid chemicals about 6,000 years ago (1, 2). These chemicals could cause both euphoria and suppress pain. Initially, these chemicals were derived from plants, like the poppy. The most common legal plant-derived opioid is morphine. The most common illegal plant-derived opioid is heroin.

More recently, opioids are made in chemical labs. Lab-derived opioids are called synthetic. The most common lab-derived synthetic opioid is fentanyl. Fentanyl is about 100 times more potent than morphine and about 50 times more potent than heroin.

Recently, a newer lab-derived synthetic opioid has appeared, nitazene. A recent headline from the Wall Street Journal was (3):

A Drug You Haven’t Heard of Is Killing Hundreds Every Year

This article states:

“The most common street nitazenes are roughly 50 to 250 times as potent as heroin, or up to five times the strength of fentanyl.”

All opioid chemicals, both from plants and chemical labs, are highly addictive, and they all interfere with breathing, the most common cause of opioid-related death.

Terminology

Tolerance:

Tolerance means that the user needs higher and/or more frequent doses of the drug to get the desired effects. Long-term use of prescription opioids, even when prescribed by a doctor, can cause some people to develop a tolerance.

Dependence:

Opioid dependence occurs with repeated use, causing the neurons to adapt so they only function normally in the presence of the drug. In the absence of the drug, physiological function is altered with sometimes intolerable side effects and symptoms.

Addiction:

Opioid addiction is a chronic disease characterized by compulsive, or uncontrollable, drug seeking and use despite harmful consequences and long-lasting changes in the brain.

Naloxone

Naloxone is a life-saving drug that is used for opioid overdose. It can rapidly reverse an opioid overdose by binding to opioid receptors and blocking the effects of other opioid drugs (4).

Opioid Crisis

As noted, humans have been using opioids for thousands of years. Yet, the modern health-crisis related to the opioid epidemic was primarily the consequence of two studies published in renowned and respected medical journals:

• The first one appeared in the prestigious New England Journal of Medicine in January of 1980. The Journal published a short letter-to-the-editor by physician Hershel Jick, MD, and his assistant Jane Porter, titled (5):

Addiction Rare in Patients Treated with Narcotics

• The second one appeared in the prestigious journal Pain in May of 1986. Respected physician and pain specialist, Russell Portenoy, MD, and Kathleen Foley, MD, both from Cornell University Medical College, published a paper titled (6):

Chronic Use of Opioid Analgesics in Non-malignant Pain:
Report of 38 Cases

This article looked at a mere 38 people who were on high-dose narcotics, and they found there was little associated addiction and/or death.

The authors reasoned that, “opioid maintenance therapy can be safe.”

They encouraged physicians to get over their fear of painkillers, what they called “opiophobia.”

• The June 15, 2015 cover article of the political magazine Time states (7):

“They’re the most powerful painkillers ever invented. And they’re creating the worst addiction crisis America has ever seen.”

“…9.4 million Americans take opioids for long-term pain.”

“Doctors so frequently prescribe the drugs known as opioids for chronic pain from conditions like arthritis, migraines and lower back injuries that there are enough pills prescribed every year to keep every American adult medicated around the clock for a month.”

“Now 4 of 5 [80%] heroin addicts say they came to the drug from prescription painkillers.”

“The American Academy of Neurology last year concluded that the risks of long-term opioid treatment for headaches and chronic low-back pain likely outweigh the benefits.”

• The November/December issue of the RandReview published an article titled Opioid Rising, which notes (8):

Heroin kills more than 8,000 Americans yearly, but opioid prescription painkillers kill more than double that number.

“The Centers for Disease Control and Prevention now considers opioid drug abuse to be a full-fledged epidemic.”

• Recent publications indicate that 78 Americans die daily from opioid painkiller overdoses (9).

Candace Pert, PhD

Candace Beebe Pert was born in 1946 (d. 2013). She was an American neuroscientist and pharmacologist, and she changed the world, for both good and for bad. In 1973, as a 26-year old graduate student working at Johns Hopkins University School of Medicine, she discovered the existence of opioid receptors, the cellular binding site for endorphins, in the brain.

Her 1973 study was published in the journal Science, titled (10):

Opiate Receptor: Demonstration in Nervous Tissue

Her work was further detailed in 1974 in an article published in the Annals of Internal Medicine, titled (11):

The Opiate Receptor

 Pert’s discoveries and neurophysiological descriptions were undoubtedly exciting for drug companies as they predated the publications by Jick, Porter, Portenoy, and Foley. Yet, Pert’s studies also showed the benefits of naloxone, the powerful opiate antagonist that today is the main intervention for opiate overdose.

The unfolding of these exciting discoveries and the logistics of the involved personalities are detailed in Pert’s 1997 book, titled Molecules of Emotion: The Science Behind Mind-Body Medicine (12).

The Brainstem

The brain is located inside of the skull. The spinal cord is located outside of the skull in the spinal column. Between the brain and the spinal column is the brainstem. The brainstem is located inside of the skull.

The brainstem has three parts:

• The midbrain, or mesencephalon, which is the highest part, is attached to the brain.
• Immediately below the midbrain is the pons.
• Immediately below the pons is the medulla oblongata. The medulla is attached to the pons above and to the spinal cord below.

Periaqueductal Gray Matter
(PAG)

In the midbrain (mesencephalon) there is a spot called the periaqueductal gray matter.

The work of Candace Pert and colleagues established that opioid chemicals work by attaching to opioid receptors that are located within the central nervous system (brain-brainstem-spinal cord). Soon, it was established the primary location for the opioid receptors for pain control, anywhere in the body, was the mesencephalon periaqueductal gray matter.

Stimulation of the periaqueductal gray matter for pain control initiates what is known as activating the Descending Pain Inhibitory Control System.

Non-Drug Influences

Although pharmaceutical companies were undoubtedly excited about the greater understanding of the periaqueductal gray matter and its opioid receptors, they did not appreciate the problems with opioid drugs as related to tolerance, dependence, addiction, and death. Nor were they interested in the physiological studies showing that one could activate the periaqueductal gray matter for important pain suppression using non-pharmacological methods. These non-pharmacological methods could be done with few or no undesirable side effects. Examples include:

• In 1977, the journal Science published a study titled (13):

Pain Relief by Electrical Stimulation of the Central Gray Matter in Humans and its Reversal by Naloxone

The authors of this study showed relief of intractable pain was produced in six human patients by stimulation of electrodes implanted in the periaqueductal gray matter. The authors suggested that satisfactory alleviation of persistent pain in humans may be obtained by electronic stimulation of “periaqueductal gray pain.”

• In his 1979 book, The Brain, The Last Frontier, Richard Restak, MD, reviews this research, stating (14):

“Within the periaqueductal gray, a deep-seated brainstem area lying along the floor of the third ventricle, neurosurgeons at the University of California in San Francisco placed indwelling stimulating electrodes for pain relief in six patients afflicted with chronic, unremitting pain. Whenever the patients began to experience pain, they were able to shut it off via the activation of a battery-operated stimulator about the size of a pack of cigarettes. After activating the stimulator, all six patients—in accordance with earlier findings in other pain patients—experienced dramatic, long-lasting, and repeatable pain relief.”

“In order to test the hypothesis that pain relief was genuine and not just an example of a ‘placebo response,’ one patient was outfitted with a stimulator containing a ‘dead’ battery. The patient, a fifty-one-year-old woman with severe back and leg pain caused by cancer of the colon, anxiously reported that her pain had returned and the stimulator ‘wasn’t working.’ Replacement of a new battery led to immediate pain relief.”

• In 1998, Barr’s The Human Nervous System, An Anatomical Viewpoint, states (15):

“Descending pathways modify the activity of all ascending systems, including responses to noxious stimuli.

The best understood of these is the raphespinal tract, which arises from neurons in the raphe nuclei of the medullary reticular formation, mainly those of the nucleus raphes magnus, and use serotonin as a neurotransmitter.

The nucleus raphes magnus is itself influenced by descending fibers from the periaqueductal gray matter of the midbrain.

Electrical stimulation of the nucleus raphes magnus or the periaqueductal gray matter causes profound analgesia.

An electrode sterotaxically implanted into the periaqueductal gray matter enables a patient to relieve pain instantly when switching on an electrical stimulator.  The analgesia often lasts for several hours after cessation of the stimulation.”

• In 1999, The Human Brain, An Introduction To Its Functional Anatomy, states (16):

“Electrical stimulation (through implanted electrodes) of the periaqueductal gray of the midbrain causes analgesia so profound that major surgery can then be performed without the aid of an anesthetic.

Stimulation of the periaqueductal gray of humans can ameliorate intractable pain.

The periaqueductal gray receives inputs from the hypothalamus and several cortical areas.

Opium and its derivatives, especially morphine, have long been used for pain control, and one way they work is by activating the periaqueductal gray-raphe nucleus pain-control system at multiple levels.

Opiate receptors are found in abundance in the periaqueductal gray, nucleus raphe magnus, and superficial laminae of the posterior horn.”

• In 2000, Functional Neuroscience, states (17):

“An important aspect of nociception is that transmission along pain pathways is modulated by descending systems.

Stimulation of the periaqueductal gray matter leads to a loss of sensitivity to painful stimuli.

This finding led to the development of therapies for intractable pain that involved stimulating the periaqueductal gray with implanted electrodes. Such stimulation alleviates pain.

Descending modulation of pain sensitivity is mediated by the descending projections from the periaqueductal gray. 

The descending circuits that modulate transmission along nociceptive pathways are thought to operate in part by using opioid peptides as their neurotransmitter.    

Opiate-containing neurons in the periaqueductal gray and medulla activate neurons that give rise to the descending pathways.”

         These studies indicate the following:

• Opiate receptors, when activated, inhibit pain.
• The periaqueductal gray matter of the mesencephalon is densely populated with opiate receptors.
• Electrical stimulation of the periaqueductal gray matter opiate receptors causes quick and complete pain relief throughout the body.

One might ask, why not treat all chronic pain patients with electrical stimulation to the periaqueductal gray matter of the mesencephalon?

Inserting electrodes into the periaqueductal gray matter requires breaching the integrity of the blood brain barrier. The blood brain barrier integrity is of utmost importance in protecting the integrity of the brain and spinal cord (18). Consequently, electrode stimulation of the periaqueductal gray is best reserved for patients needing end-of-life pain control.

Heidi Haavik, DC, PhD

Perhaps the most noted contemporary chiropractic researcher is neuroscientist Heidi Haavik, DC, PhD. As of this writing (August 12, 2025), Dr. Haavik has 80 publications indexed in the National Library of Medicine of the United States.

In 2024, Dr. Haavik and colleagues published a study in the journal Brain Science, titled (19):

Neuroplastic Responses to Chiropractic Care:
Broad Impacts on Pain, Mood, Sleep, and Quality of Life

This study evaluated the underlying neurophysiological mechanisms of chiropractic care by assessing 76 people with chronic low back pain. The authors note:

“Chiropractic care is based on the premise that correcting vertebral subluxations improves central neural function, improving human performance and clinical outcomes.”

“[Vertebral subluxation] is characterized by abnormal movement or function  of spinal segments which is identified by clinical markers such as restricted  intersegmental range of motion, tenderness upon palpation, palpable  asymmetric intervertebral muscle tension, and altered joint play and end feel.”

“Chiropractic adjustments have been shown to influence various aspects of neurophysiology, including somatosensory processing, sensorimotor integration, and motor control, all crucial for executing motor tasks accurately and recovering from central nervous system injuries.”

Chiropractic care drives neuroplastic brain changes in “structures such as the primary somatosensory cortex, primary motor cortex, prefrontal cortex [PFC], and cerebellum.”  

Chiropractic adjustments altered proprioceptive input from the paraspinal tissues which may be powerful enough to alter processing within the PFC.

Importantly, these authors suggest that chiropractic adjustments may work by activating the descending pain inhibitory control system. They state:

“It is well known that the descending modulatory pain pathway is malfunctional in chronic pain patients.”

“[This study supports] the notion that part of the mechanisms of chiropractic care is that it might improve the descending modulatory pain pathway in chronic low back pain patients, and this may be why it has been found to be clinically effective for both acute and chronic low back pain problems and is a recommended option in relevant clinical guidelines.”

Richard Ambron, PhD

Richard Ambron, PhD, is emeritus professor of pathology, anatomy, and cell biology at Columbia University. In 2022 he wrote the book (20):

The Brain and Pain: Breakthroughs in Neuroscience

In this book, Dr. Ambron notes:

“Studies show that electrical stimulation of the PAG [periaqueductal gray] could diminish pain without interfering with touch, pressure, or temperature sensations.”

“[The PAG is placed] as an essential center for the perception of pain.”

“The suppression of injury-induced pain is most likely due to the activation of the opioidergic neurons in the PAG.”

Dr. Heidi Haavik (above) indicates that the primary beneficiary of chiropractic spinal adjusting is the activation of the brain’s pre-frontal cortex (PFC). Dr. Richard Ambron indicates that the PFC is the primary driver of the PAG and the descending pain inhibitory control system. He states:

Activation of circuits within the “PFC will have a significant impact on the experience of pain.”

“The modulation of painfulness is associated with increased activity in the PFC.”

“We know that there are connections between the PFC and the PAG.”

“The activation of the PAG is controlled by circuits in the PFC.”

“Inputs from the PFC to the PAG result in the activation of the opioidergic neurons whose axions descend to the spinal cord, where the release of opioids prevents synaptic transmission at the synapse between the first- and second-order neurons in the nociceptive pathway.”

Activating the Descending Pain Inhibitory Control System with Spinal Adjusting, A Historical Perspective

In 1996, a study in the journal Pain, titled (21):

The Initial Effects of a Cervical Spine Manipulative Physiotherapy Treatment on the Pain and Dysfunction of Lateral Epicondylalgia

These authors treated elbow pain in patients who were not suffering from radiculopathy or referred pain by only manipulating the dysfunctional joints of the patient’s cervical spine. The most commonly found biomechanical dysfunction was hypomobility of the joints of the lower cervical spine. The authors note:

“This study has demonstrated a clear hypoalgesic effect of a manipulative therapy technique [applied to the cervical spine] in the period immediately following its application in a group of patients with lateral epicondylalgia.”

The authors’ theoretical model to explain their results involved manipulative therapy activation of the hypoalgesic effects of the endogenous supraspinal pain inhibitory systems.

“The [manipulative] treatment technique used in this study provided a non-noxious sensory input at the cervical spine which resulted in a reduction of elbow pain that outlasted the duration of its application.” “This is thought to activate the descending pain inhibitory system as a major component of their pain-relieving effects.”

The descending pain inhibitory system is activated by stimulation of the periaqueductal gray (PAG).

“These findings indicate that manipulative therapy may constitute an adequate physical stimulus for activating descending pain inhibitory system.”

A common finding in other studies “was the predominance of hypomobility at the lower cervical motion segments.” It is feasible that part or all of the impairments in this study were “projected from the hypomobile cervical spine motion segment(s), and that the improvements gained following application of the [manipulative] technique resulted from treating the source of the pain.” 

“Manipulative therapy [may] recruit the descending pain inhibitory system, through which it exerts a portion or all of its pain-relieving effects. That is, manipulative therapy applied to the cervical spine produces a sensory input which could be sufficient to activate the descending pain inhibitory system.”

In 2014, a study was published in the Journal of Back Musculoskeletal Rehabilitation, titled (22):

The role of the Descending Inhibitory Pain Mechanism in Musculoskeletal Pain Following High-velocity, Low Amplitude Thrust Manipulation: A Review of the Literature

The objective of this review was to investigate the role of the descending inhibitory pain mechanism in musculoskeletal pain following high-velocity, low amplitude thrust manipulation. The authors state:

“Although the antinociceptive effect of high-velocity, low amplitude thrust manipulation has been recognized by numerous systematic reviews, the underlying mechanism for manipulation-related pain relief remains poorly understood. An increasing number of studies have explored its analgesic mechanism suggesting that the excitation of the descending inhibitory pain mechanism might play the most important role for musculoskeletal pain relief.”

“Findings from current literature support that high-velocity, low amplitude thrust manipulation has a profound influence on nociceptive stimulus via the possible activation of the descending inhibitory pain mechanism. It seems that the application of this technique activates the periaqueductal gray region area of the midbrain, stimulates the noradrenergic descending system and at the level of the spinal cord, the nociceptive afferent barrage is reduced and mechanical hypoalgesia is induced.”

Summary

For decades, the periaqueductal gray matter descending pain inhibitory control system and their links to opiate receptors has been understood. Although it is proven that this descending pain control system can be activated with implanted electrodes, the inherent substantial and serious risks of such a procedure has minimized this approach, except for end-of-life pain suppression.

Opiate pharmacology for activating this pain-suppression system has become commonplace, and has resulted in a modern-day epidemic and crisis. Problems include receptor adaptation, tolerance, dependence, addiction, and death.

The evidence that chiropractic spinal adjusting can activate the descending pain inhibitory control system, especially upper cervical chiropractic adjusting (23), is an important finding. Perhaps, all chronic pain patients should be evaluated and treated chiropractically for spinal biomechanical dysfunctions. Chiropractic has proven to be helpful in chronic pain patients with almost no risk to the patient.

REFERENCES: 

1. Offit PA; Pandora’s Lab: Seven Stories of Science Gone Wrong; National Geographic; 2017.
2. Inglis L; Milk of Paradise: A History of Opium; Pegasus Books; 2019.
3. Rasmussen SE, Li M; A Drug You Haven’t Heard of Is Killing Hundreds Every Year; Wall Street Journal; July 30, 2025; p. A16.
4. https://nida.nih.gov/publications/drugfacts/naloxone. Accessed August 5, 2025.
5. Porter J, Jick H; Addiction Rare in Patients Treated with Narcotics; New England Journal of Medicine; January 10, 1980; Vol. 302; No. 2; p. 123.
6. Portenoy RK, Foley KM; Chronic Use of Opioid Analgesics in Non-malignant Pain: Report of 38 Cases; Pain; May 1986; Vol. 25; No. 2; pp. 171-186.
7. Calabresi M; “They’re the most powerful painkillers ever invented. And they’re creating the worst addiction crisis America has ever seen.” Time; June 15, 2015.
8. Irving D; “Opioid Rising.” RandReview; November/December 2015.
9. Ross C; Opioid Addiction: Effort to cut access fails to slow deaths; The Plain Dealer (Sunday, Cleveland, OH); August 7, 2016; p. A2.
10. Pert CB, Snyder SH; Opiate Receptor: Demonstration in Nervous Tissue; Science; March 9, 1973; Vol. 179(4077); pp. 1011-1014.
11. Snyder SH, Pert CB, Pasternak GW; The Opiate Receptor; Annals of Internal Medicine; October 1974; Vol. 81; No. 4; pp. 534-540.
12. Pert C; Molecules of Emotion: The Science Behind Mind-Body Medicine; Simon & Schuster; 1997.
13. Hosobuchi Y, Adams JE, Linchitz R; Pain Relief by Electrical Stimulation of the Central Gray Matter in Humans and its Reversal by Naloxone; Science; July 8, 1977; Vol. 197(4299); pp. 183-186.
14. Restak R; The Brain, The Last Frontier; Warner Books; 1979; pp. 341-342.
15. Kiernan JA; Barr’s The Human Nervous System, An Anatomical Viewpoint; Lippincott-Raven; 1998; pp. 351-352.
16. Nolte J; The Human Brain, An Introduction To Its Functional Anatomy; Mosby; 1999; pp. 270-271, p. 274.
17. Steward O; Functional Neuroscience; Springer; 2000; pp. 218-219.
18. Daneman R, Prat A; The blood-brain barrier; Cold Spring Harbor Perspectives in Biology; January 5, 2015; Vol. 7; No. 1; pp. a020412.
19. Haavik H, Niazi IK, Amjad I, Kumari N, Ghani U, Ashfaque M, Rashid U, Samran M, Nlandu E, Kamavuako EN, Amit N, Pujari AN, Kelly Holt K; Neuroplastic Responses to Chiropractic Care:  Broad Impacts on Pain, Mood, Sleep, and Quality of Life; Brain Science; November 7, 2024; Vol. 14; No. 11; Article 1124
20. Ambron R; The Brain and Pain: Breakthroughs in Neuroscience; Columbia University Press; 2022.
21. Vicenzino B, Collins D, Wright A; The Initial Effects of a Cervical Spine Manipulative Physiotherapy Treatment on the Pain and Dysfunction of Lateral Epicondylalgia; Pain; November 1996; Vol. 68; No. 1; pp. 69-74.
22. Savva C, Giakas G, Efstathiou M; The role of the descending inhibitory pain mechanism in musculoskeletal pain following high-velocity, low amplitude thrust manipulation: a review of the literature; Journal of Back Musculoskeletal Rehabilitation; 2014; Vol. 27; No. 4; pp. 377-382.
23. Garcia DV, Dierckx R, Otte A, Holstege G; PET and SPECT in Neurology, Chapter 46 “Whiplash: Real or Not Real: A Review and New Concept”; Springer-Verlag; 2014; pp. 947-963.