Neurobiology of Pain and the Mechanism of Pain Medications

Kristen Fuller M.D.

Pain does not discriminate. It affects every one of all ages, ethnicities, and social statuses. Pain comes is different forms; emotional, mental and physical. Physical pain is the most studied and the pathway involves many intricate mechanisms. There are a multitude of pain medications that act specifically on different receptors in the body. It is important to understand the different

pain pathways in order to design new pain medications and alternative therapies to heal individuals and alleviate pain from their everyday lives. Each individual is unique when it comes

to pain. Some individuals get painful piercings and tattoos; others feel immense pain when receiving an influenza vaccination. Variability among individuals is one of the main

characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perception of pain, and

response to analgesic strategies.

SECTION ONE: Introduction

According to the International Association for the Study of Pain, pain is described as “a distasteful sensory and emotional experience associated with actual or potential tissue damage”.1

Pain protects humans by warning them of occurrence of biologically harmful processes. For example, individuals protect themselves from burns, bruises and wounds primarily due to reflex activity. Reflexes which are controlled at the level of the spinal cord protect the individual by removing a body part away from the source of danger. Quickly removing a hand away from a hot stove prevents a serious potential burn injury. The skin senses the heat which quickly alerts the brain via the spinal cord and within seconds, the hand quickly moves away from the heat source. This is just one example of how a reflex helps protect the individual from pain. Fear of pain can also prevent a person from moving. For example, a painful ankle sprain can prevent an individual from bearing weight on that ankle; promoting healing of the injury and preventing anymore unnecessary pain. Associated emotional arousal, experienced as distress or fear, may also motivate a person to move away from a painful stimulus. Pain may elicit an empathic, comforting, and health promoting behavior in people observing a person in pain.

According to a report published on the Center for Disease Control website, nearly three out of four prescription drug overdoses are caused by prescription painkillers, more formally known as opioid or narcotic pain relievers.2 Painkillers are some of the most commonly prescribed medications by medical doctors. In fact, the narcotic pain medication hydrocodone/acetaminophen was the most prescribed generic medication in 2014.3 According to the news article, published on Medscape, Top Ten Most Prescribed Generic Drugs, hydrocodone/acetaminophen, commonly known as Vicodin, Norco or Lortab, had approximately 123.3 million prescriptions in 2014. Medications containing oxycodone (OxyContin) and codeine are not far behind hydrocodone. Acetaminophen is the active ingredient in Tyleonol, and although it is used as a fever reducer and a pain reliever, it is not a narcotic. However, it is used commonly in combination with narcotics such as in oxycodone/acetaminophen; commonly known as Percocet and codeine/acetaminophen; commonly known as Tylenol with Codeine #3 or Tylenol with Codeine #4, depending on the strength of the codeine. Tylenol with codeine is often used in prescription cough syrups to help with cough suppression. These 3 common pain

medications: hydrocodone, oxycodone and codeine are overprescribed and overused causing many people to become addicted to narcotics which is not only bad for physical health but is detrimental to society because of the effects such as drug trafficking, violent crime, stealing and the money it costs to stop the war on drugs.

When drugs such as opioids are repeatedly used overtime, a tolerance to opioids will develop. Tolerance is when a greater amount of a substance is needed overtime to produce the same initial response.4 A person will need a higher amount of heroin or morphine overtime to receive the same euphoric and analgesic affects. People that snort or injection opioids will develop a quicker tolerance compared to those that take opioids by mouth as prescribed. This is due to the fact that the rate of administration is much faster when a drug is snorted or injection. Physical dependence is the physiologic change the body and brain undergo as a result of opioid use overtime. A person becomes physically dependent on a drug when they exhibit physical withdrawal symptoms in the absence of the drug.4 When someone becomes dependent on opioids, they will have diarrhea, severe muscle aches, abdominal cramping, and insomnia when they stop taking the drug. All of these are common withdrawal effects of opioids.

Opioid addiction is characterized by the behavior that encompasses genetic, psychosocial and environmental factors that causes the person to continue to use opioids. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.4 Patients can develop physical dependence and tolerance to a drug but not necessarily become addicted. However most people that are addicts have already developed tolerance and dependence to that drug. Uncontrollable cravings are the hallmark of addiction and it is these cravings that cause addicts to go to extreme lengths in order to get their hands on the drug. This may include illegal and dangerous activity. Addicts often times will fail to meet social and work obligations; leading to struggles within their personal relationships and financial status.

SECTION TWO: Classification of Pain

Pain is not a universal characteristic feeling. It can present in many forms and locations depending on the mechanism of injury. There are different types of pain, depending on the type of injury and where in the body the pain is felt. Somatic, visceral and neuropathic pain are the three major categories of pain and each of these categories can be divided further into acute and chronic pain. Nociceptive pain is believed to be caused by the ongoing activation of pain receptors in either the surface or deep tissues of the body. These pain-detecting nerves, send an impulse from the painful site up through the spinal cord and to the brain for interpretation and reaction. There are two types: "somatic" pain and “visceral" pain. Somatic pain is characterized by well- localized pain that is achy or gnawing in nature. It is caused by a multitude of factors such as inflammation, repetitive trauma, excessive activity, vigorous stretching, and contractions due to paralysis, spasticity, disuse and misuse. Somatic pain can affect the skin, muscles, bones, joints and connective tissues in the body.5 Somatic pain is usually aggravated by activity and relieved by rest. The joint pain caused by rheumatoid arthritis may be considered an example of this type of somatic nociceptive pain. Other examples include tension headaches, back pain and joint pain. Somatic pain can further be divided into chronic and acute. A muscle sprain can be classified as acute pain where as back pain can be either acute or chronic, depending on the duration.

Somatic pain often involves inflammation of injured tissue. Although inflammation is a normal response of the body to injury, and is essential for healing, inflammation that does not disappear with time can result in a chronically painful disease. Inflammatory pain a result of activation and sensitization of the nociceptive pain pathway by a variety of mediators released at a site of tissue inflammation. The mediators that have been implicated as key players are proinflammatory cytokines such IL-1-alpha, IL-1-beta, IL-6 and TNF-alpha, chemokines, reactive oxygen species, vasoactive amines, lipids, ATP, acid, and other factors released by infiltrating leukocytes, vascular endothelial cells, or tissue resident mast cells.5

There are a series of 3 reactions to somatic pain: the startle response, autonomic response and the behavioral response. The startle response is a complex psychosomatic response to a sudden unexpected stimulus which include a flexion reflex, postural readjustment and orientation of the head and eyes to examine the damaged area. It is usually a very sudden response that enables the body to move away from the source of the pain. The autonomic response controlled by the autonomic nervous system where stress hormones are release in order to combat the injury. These hormones include norepinephrine, epinephrine, and cortisol. The behavioral response is the conscious response to painful stimuli that includes vocalization, rubbing designed to diminish pain, learning to respond to sudden pain and psychosomatic pain.5

Visceral pain is the other type of nociceptive pain. Visceral pain is usually referred to as internal pain and usually affects hollow organs and smooth muscle. It is mediated by discrete nociceptors in the cardiovascular, pulmonary, gastrointesitinal and genitourinal systems and is usually described as dull, achy and non-localized. In many cases, visceral pain is not localized to the site of its cause, rather in a distant site. For example, gallbladder problems can cause right shoulder pain. Unlike somatic pain, visceral pain may be harder to pinpoint. Some common types of visceral pain include stretching, distension, or ischemia of the viscera (lining of the internal organs). In cancer patients, visceral pain may be caused not only by direct tumor infiltration, but also by variable conditions such as constipation, radiation, or chemotherapy. Pain from acid indigestion is also an example of visceral pain. Visceral pain, like somatic pain can be described as chronic or acute. Examples of acute visceral pain include gallstones and appendicitis. Examples of chronic pain in the viscera is observed in functional bowel disorders such noncardiac chest pain, chronic idiopathic dyspepsia, functional abdominal pain, and irritable bowel syndrome. Chronic pelvic pain such as chronic interstitial cystitis, and painful bladder syndrome are also examples of chronic visceral pain which are multifaceted problems and are still poorly understood.6

Neuropathic is the third type of pain that is commonly described in the medicine literature. Unlike somatic and visceral pain, this type of pain is not classified as nociceptive pain. This type of pain is initiated or caused by a primary lesion or disease in the somatosensory nervous system. It is a persistent pain that arises from functional changes occurring in the central nervous system secondary to peripheral nerve injury. Once the nerve is damaged, the damaged nerve elicits sustained activation of nociceptors. The neuropathic pain is due to an abnormal activation of the nociceptive system without specifically stimulating the nociceptors. Sensory abnormalities range from deficits perceived as numbness to hypersensitivity (hyperalgesia or allodynia), and to paresthesias such as tingling. Examples include, but are not limited to, diabetic neuropathy,

postherpetic neuralgia, spinal cord injury pain, phantom limb (post-amputation) pain, and post-stroke central pain.7,8

Visceral, somatic and neuropathic pain can be further divided into acute and chronic pain, depending on the duration of the pain. Acute pain has been defined as “pain associated with tissue damage, inflammation, or a disease process that is of relatively brief duration such as hours, days, or even weeks, regardless of its intensity.” Acute pain results from disease, inflammation, or injury to tissue and is self-limited. It serves as the body’s defense mechanism to seek help right away. The sudden onset of pain after surgery or following a traumatic event may be accompanied by anxiety or emotional distress; perpetuating the emotional and pain cycle. The cause of this acute pain can usually be diagnosed and treated. It is confined to a given period of time and severity.9

Chronic pain has been defined as “pain that persists for extended periods of time (i.e. months or years), that accompanies a disease process such as rheumatoid arthritis, or that is associated with an injury that has not resolved within an expected period of time such as myofascial pain syndromes, complex regional pain syndrome, and chronic pelvic pain.”10 Chronic pain, unlike acute pain is widely believed to represent disease itself. It can be made much worse by unpleasant environmental and psychological factors. It persists over a longer period of time than acute pain and unlike acute pain; it is resistant to most medical treatments, making this a difficult disease to treat. Chronic pain has other factors besides injury and disease associated with it that prolongs its presence. These factors include continued tissue damage, loss of a body part, extensive trauma, or damage to the nervous system as a result of injury. For example, fibromyalgia patients demonstrate significantly less gray matter density than healthy controls in several brain regions, including the cingulate, insular and medial frontal cortices, and parahippocampal gyri. Patients with chronic back pain (CBP) showed 5–11% less neocortical gray matter volume than control subjects. These changes seen in the central nervous system are not uncommon in chronic pain patients. Due to these factors, the pain persists either beyond the expected course of disease, or beyond the time expected for an injury to heal, or it recurs at various times for months or years. In such situations, the injury may exceed the body’s capability to heal. Additionally, intensity of chronic pain may be out of proportion of original injury or damage, and syndromes, such as complex regional pain syndrome, may occur spontaneously without any signs of injury. It causes severe problems for the patient, not only physical but emotional and mental as well. Chronic pain impairs an individual’s social, vocational and psychological well being. Among psychological factors, chronic pain has been frequently associated with depression, which may vary from minor to severe. Depression also appears to intensify chronic pain. While some patients display depression, others maintain a dispassionate attitude. Fibromyalgia is an intractable widespread chronic pain disorder that is most frequently diagnosed in women.9

Acute exacerbations of chronic pain are characterized by pain flares and breakthrough pain. Pain flares are transient increases in pain that can last for hours to days. Flares are extremely common and generally benign although they may be perceived as harmful by the patient. Pain intensity eventually returns to baseline.1 Patients are encouraged to use behavioral and other nondrug techniques to manage flares. Care should be used with additional short-acting analgesics

since they are not appropriate from a mechanistic standpoint and may only lead to escalated use of analgesics.

Breakthrough pain (BTP) is a term first used to describe a transitory exacerbation of pain which can be either predictable or spontaneous which occurs on a background of otherwise stable pain in patients receiving chronic pain medication and therapy.1 The pain is most often seen in cancer patients who are suffering from chronic visceral and somatic pain. The term is often over-used in clinical practice to describe any increase in pain; this can be confusing. Increases in pain may be categorized as incident related such as caused by movement, cough or defecation, end-of-dose failure, or idiopathic. It is important to understand that all pain is dynamic and can fluctuate. Physicians should assess the characteristics of increases in pain in an attempt to identify its pathophysiology, predictability, onset, intensity and duration in order to apply appropriate treatment and differentiate between a pain flare or disease progression.

In order for the human body to experience pain, receptors in the body must be stimulated and they also must have the capacity to send signals to the central nervous system. As described earlier, nociceptive fibres are the fibers that carry pain signals in response to a stimulus that is strong enough to threaten the body’s integrity. These nociceptive fibers do not have detailed internal structures; instead they have what are known as free nerve endings. These free nerve endings form dense networks with multiple branches that are together are regarded as nociceptors. There are various types of nerve fibres whose free endings form nociceptors. These fibres all connect peripheral organs to the spinal cord, but differ greatly both in diameter and in the thickness of their myelin sheath that surrounds them.10 Both of these traits affect the speed at which these axons conduct nerve impulses: the greater the diameter of the fibre, the thicker its myelin sheath, and the faster this fibre will conduct nerve impulses. These fibers have been classified into three types based on their diameter, myelination and conduction velocity: the A (with four subtypes – α, β, γ and δ), B and C-fibers. The A-δ fibers and C-fibers conduct pain signals, but, at different velocities. A-δ fibers which are myelinated, conduct fast pain (a sensation experienced immediately after an injury that indicates location of injury). C-fibers which are unmyelinated, conduct slow pain (follows sharp pain and can be characterized as a dull, throbbing ache with poor localization).11,12

SECTION THREE: Pain pathway and Pain Matrix

In order to understand the science behind pain, it is important to outline the pain pathway and the anatomical and physiological aspects that play a major role in body’s reaction to pain. The entire structure described is referred to as the pain matrix. There are 5 specific parts of the nervous system that transmit pain signals from the periphery to the higher centers of the central nervous system. A noxious stimulus originating in the periphery travels through multiple transmission systems to reach various parts of the central nervous system. These pathways and transmission systems are quite complicated and the central nervous system does not receive a noxious stimulus passively. Rather, it processes this stimulus using various regulatory mechanisms.

Nociceptors are one type of somatosensory receptors that are first order neurons of the pain pathways. These receptors generate pain signals through their free nerve endings in response to harmful stimuli. Different types of nociceptors have been identified that respond to mechanical, heat and chemical stimuli, or any combination of these stimuli. Cell bodies of these nociceptors reside in the dorsal root ganglia (DRG). The dorsal root ganaglia lie in the posterior root of a spinal nerve. These spinal nerves run alongside the vertebral column. Nerve fibers leaving the DRG bifurcate and send one branch to the periphery and the other branch to the dorsal horn (DH), which is located in the grey matter of the spinal cord. The peripheral fibers conduct pain signals from the skin, muscles, fascia, vessels, and joint capsules to the dorsal root ganglia.12 INFOGRAPHIC

The dorsal horn neurons are the second part of the pain pathway. These are located in the spinal cord and act like a relay system, relaying signals from the dorsal root ganglion to the ascending spinal tracts. Nociceptors synapse on the dorsal horn neurons in the spinal cord and the second order neurons originate from this location. In the dorsal horn, this axon synapses with the second order neuron which in turn will cross the spinal cord through the anterior white commissure and ascends through the lateral spinothalamic tract to the thalamus. Different ascending tracts conduct fast and slow pain signals. Fast pain travels via the neospinothalamic tracts. The fast pain transmitting A-δ fibers predominantly terminate on the nociceptive specific neurons (NS). Slow pain travels via multiple parallel ascending pathways. The slow pain transmitting C-fibers terminate on interneurons in the dorsal horn.13

Supraspinal projections are next in the series of the pain pathway. These projections help conduct signals from the spinal cord to the thalamus. The nociceptive specific (NS) neurons are one example of supraspinal projections that conduct fast pain, and mostly end in the ventral posterolateral (VPL) nucleus of the thalamus. Third order neurons arise from the VPL nucleus and project to the primary somatosensory cortex (SI) and the secondary somatosensory cortex (SII). These projections allow for interpreting sensory features of pain, which includes location, intensity and quality of pain. The tracts conducting slow pain (the spinomesencephalic, spinoreticular, and paleospinothalamic tracts) terminate in different areas of the brain. The spinomesencephalic tracts conduct pain signals to the superior colliculus and periaqueductal gray and finally to the hypothalamus and raphe nuclei.14,15 These areas assist in turning the eyes and head towards the noxious stimulus. Together, activity in the spinoreticular and paleospinothalamic tracts results in arousal, withdrawal, and, autonomic and affective responses to pain. Several supraspinal centers are involved in processing and modulating pain signals, and can be divided into: subcortical and cortical areas. The subcortical areas most notably activated by pain signals include thalamus, basal ganglia, and cerebellum. Commonly reported cortical areas include somatosensory cortices (SI and SII), anterior cingulate cortex and insular cortices, prefrontal cortex, and motor and pre-motor cortex. 15

The thalamus is one of the supra-spinal structures that has been extensively investigated as it receives projections from multiple ascending pathways.The thalamus contains nerve centers responsible for vision, hearing reflexes, equilibrium and posture. It also relays pain signals to the cerebrum. Crude sensation reaches consciousness in the thalamus. In the thalamus, the second order neurons synapse with the third order neurons, which ascend through the internal capsule to the cerebral cortex which is responsible for the higher thought processes such as emotion and interpretation. The sensory and motor cortices are the two major components in the cerebral cortex that are responsible for the processing of pain. The thalamus relays information to the sensory cortex, which interprets the information as pain and directs the nearby motor cortex to

send information back to the thalamus.16 This is the start of the efferent or the descending pathway as the neurons will be descending down from the brain to the spinal cord. The signals travel back down the spinal cord through interneurons and eventually send signals to motor neurons in the periphery to cause a physical reaction to pain. For example, this reaction signals a response such as removing the finger from the pain stimulus such as the hot stove or out of the dog’s mouth. These motor neurons also enable other reactions from the body such as vocalizing the pain by screaming “ouch”.

Based on positron emission tomography (PET) imaging studies, the areas that are most often cited as being a part of a pain matrix include the anterior cingulate, insular, prefrontal, inferior parietal, primary and secondary somatosensory (SI and SII), and primary motor and premotor cortices. In actuality, it may be that the “wholeness” of the entire pain matrix is really the most important issue in pain. For example symptoms of pain may occur in the body whenever there is damage anywhere within the circuit-like neural matrix. It can be viewed as puzzle pieces that fit together and when there is a missing piece, the puzzle is not complete and the entire pictorial image cannot function.17, 18

Wallenberg’s Syndrome is a good example of how a single lesion in one portion of the pain matrix might lead to significant abnormal pain processing. In this condition, a lateral medullary infarct results in unilateral central pain, including allodynia on the side of the body opposite to the infarct, as well as opposite hypoesthesia to noxious and thermal stimuli. Allodynia can lead to the triggering of a pain response from stimuli which do not normally provoke pain. For example, exposure to cold can present as a burning sensation. This usually occurs after injury to a site. The neuropathic pain seen in Wallenberg’s syndrome might relate to an over-activated thalamus, which then hyper-amplified neural input to the higher pain centers, including Somatosensory cortex I and II, the insular cortex, and the anterior cingulate gyrus. For example if there is a lesion in the right lateral medulla, pain can be elicited from a non-painful stimuli and this pain is felt on the left side of the body. The left side of the body will also have a decreased sensation in temperature.19

The basal ganglia is a limbic structure in the brain that plays a crucial role in the control of voluntary movement and works closely with the thalamus, cerebral cortex and the cerebellum. : It is thought that the basal ganglia may be part of the pain matrix. Evidence from neuroimaging studies have revealed the presence of acute bilateral basal ganglia lesions in uremic diabetic patients. As a result of these lesions, these patients have developed hyperalgesia in addition to the anticipated Parkinson-like movement disorders that are generally seen in basal ganglia pathology. Some patients with basal ganglia disease such as Parkinson's disease and Huntington's disease have alterations in pain sensation in addition to motor abnormalities. Frequently, these patients have intermittent pain that is difficult to localize.20

SECTION FOUR: Regulation of Pain

Pain can be regulated and augmented through multiple complicated pathways. Pain can be decreased, increased or elicited through non-pain provoking stimuli via multiple mechanisms. Attenuation means to weaken or reduce a force through a series of signals. This word is commonly used to describe the down regulation of pain. Some studies have shown that mindfulness can play a pertinent role in attenuation. Pain accentuation is also a process that can occur. These active processes include several regulatory mechanisms that participate in

attenuating or accentuating the perception of a noxious stimulus. An accentuated pain experience can be associated with factors such as edema, fear, anxiety, and release of endogenous chemicals that sensitize nerve endings. There may also be other manifestations of pain related to tissue injury including hyperalgesia, an exaggerated response to a noxious stimulus, and allodynia, the perception of pain from normally innocuous stimuli. Hyperalgesia and allodynia are the result of changes in either the peripheral or central nervous systems, referred to as peripheral or central sensitization, respectively. In other words, these are abnormal reaction to normal stimuli. Hormonal and neuronal mechanisms play a major role in the regulation of pain.1,21,22,23

Two classic examples of pain attenuation are as follows: after injuring a hand, a person may shake it vigorously to reduce pain sensation or an athlete, although injured during a game, may not feel injury related pain until end of game. The action of β-endorphin (BE), which is formed by the hypothalamo-pituitary-adrenocortical (HPA) axis, attenuates pain resulting from injury in situations such as accidents, disasters, or athletic contests such as an athlete being injured in the game. In such situations, an injured person may have a delayed onset of pain, for example, pain begins at the end of an emergency or a contest. A delayed pain results partly because of the endorphins that act as a potent analgesic lasting a few hours. The release of these endorphins from the HPA axis, in presence of a noxious stimulus, can be explained by a group of neuronal projections. These projections include pathways ascending from the second order pain neurons in the dorsal horn of the spinal cord to the medial and lateral hypothalamus and the periventricular gray matter in the hypothalamus. The periventricular gray matter, which acts as the coordinating center of the HPA axis, responds to noxious stimuli (received from ascending pathways originating in the dorsal horn) by initiating a complex series of events regulated by feedback mechanisms. In response to noxious stimuli, the periventricular gray synthesizes and releases corticotropin-releasing hormone (CRH) into the portal circulation. This then stimulates the anterior pituitary gland to secrete several neuropeptides into the systemic circulation. These neuropeptides include adrenocorticotrophic hormone (ACTH) and endorphins. The Beta endorphin binds with opiate receptors in the brain and the dorsal horn to produce analgesia. The amount of endorphins produced is regulated by ACTH, which stimulates the adrenal cortex to release corticosteroids such as hydrocortisone and corticosterone. These corticosteroids provide neative feedback to the regulatory processes by inhibiting the anterior pituitary, which represses the formation of pro-opiomelanocortin, thereby attenuating further secretion of endorphins and ACTH . Hence hormones play a major role in pain modulation.24 Although the hormonal role is important, the neuronal role is also equally important to pain modulation.

The neuronal mechanism of this abnormal pain response can be divided into three basic parts: allodynia, the wind-up phase, and the central sensitization phase. Allodynia is an exaggerated physical response in the form of pain when a normal innocuous stimuli that usually does not provoke pain, causes pain in the body.1 This is primarily due to a lowered threshold in the afferent nociceptors. An intense, repeated or prolonged stimulation takes places and as a result the threshold for primary nociceptors is lowered and therefore the frequency of firing stimuli is increased causing a more intense pain. A common example is the pain produced after a sunburn when a light breeze causes the skin to feel even more burned or when a t-shirt simply causes the skin to feel on fire. A light breeze or a cotton t-shirt obviously do not normally elicit pain but in the case when the nociceptors are at a heightened sensitivity; this can elicit an over exaggerated pain.22,23

The wind-up up phase occurs when a stimuli occurs over and over again making the physical response even more intense. A common example is when a person touches a hot plate

over and over again and it eventually becomes painful. This occurs because the low frequency repetitive stimulation of C-fibers which are known as slow fibers produce a gradual increase in the discharge frequency of wide dynamic range (WDR) neurons until they are in a state of nearly continuous discharge. In this state of continuous discharge, there is an augmented response to input and enlarged receptive fields. Input from areas that previously did not activate the WDR neuron can now evoke a prominent response, and lower the threshold. Wind-up is elicited by any prolonged or intense C-fiber input.25

Central sensitization causes an increased responsiveness of the dorsal horn neurons resulting in enhanced conduction of pain signals to the brain. After an injury, an area of undamaged skin adjacent to the damaged tissue can evoke pain by either an innocuous stimulus (secondary allodynia) or by a previously painful stimulus (secondary hyperalgesia). The nociceptors supplying area of secondary allodynia and hyperalgesia are not sensitized. However, central sensitization occurs due to input from nociceptors that supply the area that is damaged. Input from these nociceptors leads to a transient central sensitization.26

SECTION FIVE: Nature vs. Nurture of Pain: How Environmental Factors can Influence Pain Perception

So far this paper has focused on the biological nature of pain and the mechanism of pain perception via the brain and the rest of the nervous system. The external environment via cultural heritage and lifestyle habits have shown to have a string influence on pain. Hereditary and epigenetics also play an important role in pain perception, however these will not be discussed in this current paper.

For anyone who has traveled abroad to different countries with different cultures and has witnessed ceremonial celebrations, it is apparent that there are cross-cultural differences in the coping mechanism of pain. Painful rituals such as circumcision and branding are performed everyday in many African cultures without any anesthetic and as a result these cultures have learned to develop stocicism from early childhood.27 Children are taught to embrace these painful ceremonial rituals and to not express their pain outwardly. On the other hand, many western cultures have been taught to express their pain vocally. For instance on the labor and delivery wards in the United States it is not uncommon to hear ear piercing screams from the labor halls and verbalizing labor pains is widely accepted among Americans. Allowing American children to cry after they stub their toe is on the other end of the spectrum from inhibiting vocal reactions during circumcisions in East Africa. This cross-cultural dichotomy to the expression of pain has been studied in multiple experiments between African-Americans and non Hispanic Caucasians and has revealed that there is a difference in the not only the expression of pain but the pain tolerance levels using heat and cold stimulation, and pressure and ischemic controlled stimuli.28,29

Life style habits such as exercise, smoking, and drinking also contribute to the human pain perception. Exercise can be both a treatment and a stimulus to pain, in such that too much exercise increases pain, while too little exercise may worsen pain through multiple mechanisms such as poor posture and deconditioned muscle microtrauma.30 Exercise activates endogenous analgesia in healthy individuals and clinical patients via triggering the release of beta-endorphins from the hypothalamic-pituitary axis which in turn enables analgesic effects by activating μ-opioid receptors throughout the brain and the body. The term “runner’s high” is tested and proven and can be explained through this mechanism. Therefore, exercising and movement modification during daily activities are effectively used for various chronic pain disorders,

including fibromyalgia, chronic back pain, osteoarthritis and rheumatoid arthritis. Accordingly, people who exercise sufficiently on regular basis may experience pain differently compared to non-exercising individuals, due to direct analgesic effect and also indirectly through psychological mechanisms such as improvement of mood.31 Studies have shown that chronic pain and depression often co-habituate. People who exercise are less likely to have depression and also will have lower pain thresholds compared to people who are sedentary.

Cigarette smoking and alcohol also have a complex relationship with pain. On the one hand, both nicotine and alcohol have analgesic properties. In general, nicotine administration via nasal spray or transdermal patches reduces pain sensitivity in both smokers and nonsmokers likely resulting from the effects at the nicotine acetylcholine receptors in the brain and spinal cord.32 Likewise, orally administered ethyl alcohol in equivalence to two cocktails, has been sown to produce the same tolerance to experimentally induced pain compared to approximately 12 mg of morphine in a 70kg person.33 However, multiple clinical pain studies have shown that smokers and drinkers are at increased risk of developing back pain and other chronic pain disorders such as low back pain, arthritis and other chronic pain conditions.

SECTION SIX: Pharmacological Treatment of Pain

There is an unlimited plethora of pain medications that can help alleviate pain and work by different mechanisms. Each one of the option has its own pro’s and con’s. Because pain is often individualized different pain medications have different effects in each person. Tolerance and dependence to these pain medications may arise at different treatment duration and dosages.

Opioids also known as narcotics are probably the most widely known pain medications worldwide. Heroin, morphine, oxycodone and hydromorphone are all specific types if pain alleviating medications that fall under the opiate category. Opioids date back to the 17th century. They are naturally occurring substances that are found in nature and are derived from the opium poppy plant, which has been used for hundreds of years, even dating back to the civil war era. In 1806, the active ingredient in opium was isolated and it was called morphine, after the Greek god of dreams, Morpheus.34

Opioid receptors bind opiates and as a result allow the release of neurotransmitters and endorphins resulting in analgesia. The mu- opioid receptors are the most common type of opioid receptors in the body. These receptors are most commonly found in the brain, spinal cord, and the gastrointestinal tract. The body makes natural opioids known as endorphins, which attach to their receptors in the brain and spinal cord to help alleviate pain. Opioids bind to these receptors in the thalamus, spinal cord and brainstem which are the main components in the pain pathway. It is in this pain pathway that opioids give the analgesic effect. Specifically, opioids enter the blood stream and travel to the brain where they specifically bind on mu-opioid receptors in the ventral tegmental area (VTA), nucleus accumbens, and the cortex in order to produce a sense of analgesia and euphoria. These parts of the brain are known as the mesolimbic pathway and are commonly referred to as the “reward center” of the brain. This reward center is responsible for the addiction process in the brain. When opioids bind to their receptors in all these regions, they produce a large amount of dopamine, which is the primary neurotransmitter released in the addiction and the pain pathway causing euphoria and analgesia. This euphoric effect also appears to involve another mechanism involving the GABA-inhibitory interneurons located in the ventral tegmental area .By attaching to their mu receptors, exogenous opioids reduce the amount of GABA released. Normally, GABA reduces the amount of dopamine released in the nucleus

accumbens. By inhibiting this inhibitor, the opiates ultimately increase the amount of dopamine produced and the amount of pleasure felt.34,35

The Drug Enforcement Administration(DEA) has elicited a substance control act where drugs are classified into 5 distinct categories depending upon the drug’s acceptable medical use and the drug’s abuse or dependency potential. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychological and physical dependence. As the drug schedule increases in number such as Schedule II, Schedule III, etc., the abuse potential decreases. For example, Schedule V drugs represent the least potential for abuse. Schedule I drugs include illegal drugs such as heroin, LSD, marijuana an ecstasy. Schedule II drugs include the strongest prescription drugs that physicians are allowed to prescribe such as methadone, hydromorphone and fentanyl. These schedule II drugs are the most commonly prescribed opiates and as a result have the some of the greatest potential for abuse and overdose.36,37

Opiates are just one type of medication used to relieve pain. Non-narcotic medications have less abuse potential and many do not require a prescription. These classes include acetaminophen, traditional non-steroidal anti-inflammatories such as ibuprofen and naproxen, the newer COX-2 inhibitors like celecoxib, popularly known as Celebrex and adjunctive analgesics such as steroids, anti-depressants, benzodiazepines, muscle relaxants, and local injections such as nerve blocks and lidocaine.38

The common non-narcotic medications used to treat pain are the non-steroidal anti-inflammatory agents (NSAID’s) which include aspirin and ibuprofen; and acetaminophen commonly known as Tylenol. Non-opioid analgesics work by inhibiting an enzyme known as cyclooxygenase (COX). COX is a catalyst for the conversion of a fatty acid contained in cell walls, arachidonic acid, to substances known as prostaglandins. Prostaglandins play a major role in inflammation. Prostaglandins serve a number of protective functions in the body, but they can also produce pain, inflammation and fever. They cause pain and inflammation after cell injury by a number of mechanisms, primarily at the site of the injury in the peripheral nervous system, that is, nerves outside the brain and spinal cord, but also in the central nervous system. They elevate body temperature by affecting the heat regulating center of a region of the brain known as the hypothalamus. By blocking COX and, therefore, the subsequent production of prostaglandins in the central and peripheral nervous systems, non-opioid analgesics reduce both fever and inflammation. 39,40

There are two isoforms of the COX enzyme. The most important differences between the two isoforms are the regulation and expression of the enzymes in various tissues:COX-1 is expressed in most tissues, but variably. It is described as a "housekeeping" enzyme, regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function), and it is stimulated by hormones or growth factors. COX-2 is constitutively expressed in the brain, in the kidney, in bone, and probably in the female reproductive system. Its expression at other sites is increased during states of inflammation. Both COX isoforms are regulated by physiologic stimuli, including shear stress in the vasculature and ovulation and implantation in the female reproductive tract.39

Ibuprofen, naproxen, indocen, and aspirin are some of the most commonly used NSAID’s. Ibuprofen in the most common and hence will be discussed specially in this paper. Ibuprofen was the first member of Propionic acid derivatives introduced in 1969. It is a popular over the counter analgesic, anti-inflammatory agent and antipyretic for adults and children40,41. It is a non-

selective inhibitor of cyclo-oxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2). Medical conditions that have shown an increased benefit with the use of NSAID’s include osteoarthritis, ankylosing spondilytis , sports injuries, headaches, toothaches, and menstrual cramps. Although they have some anti-pyretic effect, their primary purpose is to reduce pain and inflammation. Aspirin has some benefits that other NSAIDs do not. The biggest is that aspirin works against the formation of blood clots. As a result, you are less likely to form the clots that can cause heart attacks and strokes. Other NSAIDs do not have this effect. It is recommended that women 55 years or older and men 45 years or older take a daily baby aspirin (81mg) in order to prevent stroke and myocardial infarctions (heart attacks).40,41

NSAID’s are great pain relievers and anti-inflammatory agents however they do come with adverse side effects. NSAID’s should be used cautiously because they do have some serious side effects. NSAID’s are notorious for causing gastrointestinal ulcers leading to gastrointestinal bleeding. NSAID’s can also cause kidney disease, specifically acute tubular necrosis and acute renal failure. NSAID’s should not be used in children under 6 months of age unless for specific cases that are indicated by a physician. Aspirin, in particular should be given to children because it can Reye syndrome which is characterized by acute encephalopathy and liver failure. It is not unheard of to have allergies to aspirin. Individuals who have nasal polyps and allergies should be cautious when taking aspirin. In general, NSAID’s should only be used when needed.40,41

Acetaminophen is commonly known by its brand name Tylenol and belongs to a class of painkillers known as non-opioid analgesics. Acetaminophen is not a NSAID and therefore differs from the other non-opioids in that it does not block COX in the peripheral nervous system to an appreciable extent. It appears to reduce pain primarily in the central nervous system by more than one mechanism, possibly in part by inhibiting a form of COX known as COX-3, although this is the subject of much debate. It is, therefore, considered to be a weak analgesic and does not possess anti-inflammatory properties. What this means is that acetaminophen is great for headaches, fevers and minor aches and pains, but won’t reduce inflammation due to, say, a muscle sprain. Acetaminophen is the primary agent used for fever reduction. Acetaminophen overdose can occur. Acetaminophen is primarily metabolized by the liver. For healthy normal individuals, acetaminophen should not exceed 4g/day. It is at this level that liver failure from acetaminophen toxicity can occur. In the elderly population and patients with liver and kidney problems, acetaminophen should be limited to an even smaller daily amount. Keep in mind that acetaminophen is one of the only medications that can be administered to children at any age.40,41

In addition to NSAID’s and Ibuprofen, there are many adjunctive non-narcotic therapies that are used to treat pain. Some of the adjunctive analgesics include steroids, anti-depressants, gabapentin, muscle relaxants and local injectable anesthetics. Glucocorticoids, commonly known as steroids, reduce pain by inhibiting prostaglandin synthesis, and reducing inflammation as a result. These synthetic drugs closely resemble cortisol, a hormone is made by the hypothalamis-pituitary-adrenal axis. Glucocorticoids can cross the blood-brain barrier meaning that they have easy access into the brain where they can bind to receptors and reduce spontaneous discharge from injured nerves causing relief in neuropathic pain. These steroids can be used as a topical cream, an oral medication or as an injection.

Dexamethasone is the most commonly prescribed corticosteroid for pain, but prednisone or prednisolone can also be used. Conditions that can benefit from steroids include arthritis, joint pathology, spinal cord compression, lupus, inflammatory muscle and vascular conditions such as

polymyalgia rheumatica and systemic vasculitis. Intra-articular corticosteroids can be injected into joints in order to reduce joint inflammation and pain. Because the body makes its own steroids, giving exogenous steroids will depress the body’s internal adrenal axis and the body will eventually stop making steroids potentially causing an adrenal crisis. Therefore, steroids should be used over a short duration and in the lowest potency possible. Other side effects that are caused by steroids include gastrointestinal bleeding, increased weight gain, psychiatric side effects such as delirium and depression, osteoporosis and proximal muscle weakness. After approximately 10 days of therapy with a steroid it can be discontinued without any adverse effects. However, even low doses of corticosteroids can suppress the hypothalamic-pituitary-adrenal axis in the long term. Longer periods of treatment require a taper, the length of which depends on the duration of steroid therapy.42

Chronic pain and depression are highly prevalent conditions whose symptoms overlap and therefore using anti-depressant to treat chronic pain can also help treat depression as well. Major depressive disorder is a multifaceted disease that presents with both emotional symptoms such as depression, guilt, and suicidal ideation as well as physical symptoms such as sleep disruption, gastrointestinal disturbance, and unexplained aches and pains.43 Therefore, headache, neck and back pain, abdominal pain, and musculoskeletal pain are common in patients with depression. Antidepressants that work upon norepinephrine (NE) receptors and serotonin receptors such as serotonin-norepinephrine reuptake inhibitors (SNRIs) have been shown to decrease chronic pain. Duloxetine and venlafaxine are both SNRIs that have been shown to be effective for relieving pain that is associated with depression. Additionally current evidence based guidelines recommend the use of tricyclic antidepressants (TCA’s) and SNRIs for patients with neuropathic pain such as in patients with diabetic neuropathy. When a TCA is used, secondary-amine TCAs such as nortriptyline and desipramine are preferred agents because they are better tolerated than tertiary-amine TCAs such as amitriptyline and imipramine and have comparable analgesic efficacy.43,44

Gabapentin is a great alternative used to treat neuropathic pain. It was initially used for seizures however it has been shown to have better efficacy in treating pain associated with neuropathy such as fibromyalgia, diabetic neuropathy and postherpetic neuralgia. It’s specific mechanism of action is unknown however it is believed to block voltage gated calcium channels therefore modulating the excitatory neurotransmitters. Side effects include somnolence and dizziness. This medication is not associated with physical dependence and therefore has a very low potential for addiction.44,45

Skeletal muscle relaxants are a broad class of pharmacological agents used for the treatment of muscle spasticity, although many of these agents cause a high degree of sedation. Muscle relaxants are commonly used to treat low back pain or neck pain however their efficacy is not as good as other classes of pain relievers and they have a susceptibility for physical dependence, tolerance and addiction. Evidence for the use of tizanidine (Zanaflex) and cyclobenzaprine (Flexeril) has shown benefit as short-term treatment agents, whereas evidence for the use of baclofen and dantrolene (Dantrium) in acute treatment is limited, and there is no evidence for carisoprodol (Soma) or chlorzoxazone.46,47 Potential adverse effects from the long-term use of skeletal muscle relaxants include sedation, addictive potential, and hepatotoxicity. Evidence for acute treatment for each of these drugs is less than a month. Many of these muscle

relaxants are considered schedule 4 drugs by the DEA because they either have tolerance, dependence or addiction properties.

SECTION SEVEN: FUTURE PAIN TREATMENTSPain is a debilitating symptom associated with multiple illnesses and there are many

current, ongoing studies that are being performed and evaluated in order to improve pain management and deter away from opioid medications. In a 2011 study, physicians and scientists found a new opioid derivative, IBNtxA, which they generated in the laboratory which could be developed into a painkiller that retains the beneficial properties of opioids while avoiding their drawbacks. This investigational compound produced powerful analgesic effects without inducing breathing difficulties or physical dependence, or activating the reward pathway in the brain and causing an intense high. IBNtxA acts on a similar cellular receptor as opioids, which is known as a protein coupled G-receptor. However IBNtxA acts on a truncated or shortened G-coupled receptor thereby acting under a different mechanism than traditional opioids. This medication class has also been shown to treat neuropathic pain. This has led researchers to concentrate on truncated G couple-receptors as targets for pain therapy.48

Another interesting ground breaking invention in pain relief is the production of opioids from yeast. Researchers as Stanford University have been able to make a very expensive medication used to treat pain from a very simple ingredient often made from beer and wine. This opens the door to worldwide affordable pain management. Opioids are generally expensive hence why they are primarily used in developed countries for pain. But what about people in developing countries who cannot afford expensive therapy to relieve their pain? By using yeast to make opioids, this money gap in societies is one smaller step closer to being closed. It can take more than a year to produce a batch of narcotic pain medicine, starting from the poppy farms in Australia, Europe and elsewhere that are licensed to grow opium poppies. Plant material must then be harvested, processed and shipped to pharmaceutical factories in the United States, where the active drug molecules are extracted and refined into medicines. "When we started work a decade ago, many experts thought it would be impossible to engineer yeast to replace the entire farm-to-factory process," said senior author Christina Smolke, an associate professor of bioengineering at Stanford. Although the output of narcotics from yeast is incredibly small, for example it would take approximately 4500 gallon of yeast to produce a single dose of painkiller, it can be done. Devising a way to make this sustainable can change the international world of pain medication.49

SECTION EIGHT: Sovereign Healthcare and Addiction to Narcotics Sovereign Health group is a nationwide treatment group that is dedicated to treating addiction and mental disorders. Many of the addictions encompass narcotics. Many patients enroll in treatment programs at Sovereign Health Group because they have been prescribed narcotics for chronic pain and have become addicted and do not have the means to be able to wean themselves off of these pain medications. Unfortunately, “quitting cold turkey” has a poor success rate; fewer than 25 percent of patients are able to remain abstinent for a full year. This is where medication-assisted treatment options like methadone, naltrexone, and Suboxone can be used to treat opioid dependence by reducing the side effects of withdrawal and curbing cravings which can lead to relapse. Sovereign Health group employees physicians who are boarded in addiction medicine to help patients become clean of opioid medications. Sovereign has a multitude of

treatment options, two specifically are natural assisted detox (NAD) and medication assisted treatment.

Natural Assisted Detoxification (NAD) is a combination of Neurotransmitter Restoration (NTR) and Nicotinamide Adenine Dinucleotide (NAD) therapy that delivers vitamins, minerals and amino acids to the brain through oral or intravenous administration in order to help repair these connections in the brain, promote brain cell healing and ease the physical painful side effects of withdrawal. NTR specifically uses the mixture of vitamins, minerals and amino acids to create new neurotransmitters which are the chemicals that send signals to regulate mood and emotions in people. Examples of neurotransmitters involved in the addiction process are dopamine, serotonin and norepinephrine, all of which positively contribute to mood, sleep and concentration. These neurotransmitters are depleted when the addictive substance is eliminated from the body and therefore this natural therapy helps restore these important chemicals for proper brain function to occur. Nicotinamide Adenine Dinucleotide (NAD) is a coenzyme that is used in all aspects of energy producing cycles in the human body. It helps promote cell growth, cell function and allows the body to create a chemical known as Adeninine Triphosphate (ATP) which is the energy building block of life. Although every cell in the body requires NAD for energy and growth, the brain uses ten times more NAD energy than any other organ. NAD can be synthesized from simple building-blocks from the amino acids tryptophan or aspartic acid. Niacin, more commonly known as vitamin B3 is also a precursor for NAD.

According to the 2013 National Pain Report on Suboxone, over three million Americans with opioid dependence have been treated with Suboxone and this drug is now the 41st most prescribed drug in the U.S. Five years ago, it was the 196th most prescribed. The most important ingredient is buprenorphine, which is classified as a ‘partial opioid agonist. A ‘partial opioid agonist’ such as buprenorphine is an opioid that produces less of an effect than a full opioid when it attaches to a mu-opioid receptor in the brain. Oxycodone, hydrocodone, morphine, heroin and methadone are examples of ‘full opioid agonists’. Buprenorphine has a high affinity for and a slow dissociation from mu-opioid receptors and as a result, tricks the brain into thinking that a ‘full opioid agonist’ like oxycodone or heroin is in the same receptor. When buprenorphine is stuck in the receptor, the problem ‘full opioids’ can’t get in and this suppresses the withdrawal symptoms and cravings associated with the problem opioids. Because of this partial activation, chronic opioid users are less likely to abuse buprenorphine because it does not cause euphoria in opioid dependent patients, no matter how much of the medication they take. Because of this high affinity, buprenorphine also displaces opioids from the mu receptor, causing withdrawal in patients who have used problem opioids in the past 24 hours.50,51

The second ingredient in Suboxone is naloxone which is an ‘opioid antagonist’ or an opioid blocker. Naloxone can also bind to the mu-opiod receptor and when taken alone, can cause severe withdrawal in opioid dependent patients. Naloxone is not absorbed into the bloodstream to any significant degree when Suboxone is taken correctly by allowing it to dissolve under the tongue. However, if a Suboxone tablet is crushed and then snorted or injected the naloxone component will travel rapidly to the brain and knock opioids already sitting there out of their receptors, causing a significant withdrawal. Naloxone has been added to Suboxone for only one purpose – to discourage people from trying to snort or inject Suboxone.51.52

By implementing natural assisted detox and medicated assisted treatment; Sovereign Health group has become one of the revolutionary leaders in addiction medicine. They believe in treating the individual, not the addiction. They also offer other therapies such as group therapy, equine therapy, and yoga therapy to help calm the mind down and control the body’s cravings.

SECTION NINE: Conclusion

As previously stated, pain does not discriminate and can have potential to affect any one person at any age. It can be debilitating if it is not treated properly. However, with the right therapy and mindset, living with chronic pain is attainable. Alternative therapies such as group counseling, acupuncture, water aerobics, yoga and proper exercise can help one live and cope with chronic pain. The anatomical, physiological and pathological processes of pain in the brain and the body is extremely complicated and there is so much more to understand and reveal that this is a huge area of present research and will continued to be studied. An important aspect of chronic pain is to prevent chronic pain. Simple things such as practicing safety measures like wearing proper helmets, seatbelts and not practicing excessive risks can prevent one from an accident that can result in chronic pain. Refraining from excessive alcohol use, tobacco smoking and drug use and eating healthy while exercising can protect the body from toxins and painful injuries. Furthermore, it is important to be aware of the common over the counter medications that are used to alleviate pain. With continuing research across the globe, hopefully a safer and more effective treatment for pain can be established.

SECTION TEN: About the Author

References:

1. Part III: Pain Terms, A Current List with Definitions and Notes on Usage Classification of Chronic Pain, IASP Task Force on Taxonomy 2nd edition (209-214).

2. National Vital Statistics System, 1999-2008; Automation of Reports and Consolidated Orders System (ARCOS) of the Drug Enforcement Administration (DEA), 1999-2010; Treatment Episode Data Set, 1999-2009.

3. Brown, Tony RN. Top 10 Most Prescribed Generic Drugs Through September. Nov 6 2014.

4. Heit, Howard. Addiction, Physical Dependence, and Tolerance. Journal of Pain & Palliative Care Pharmacotherapy. 2003;17(1).

5. Cervero F. Visceral versus somatic pain: similarities and differences. Dig Dis. 2009;27 Suppl 1:3-10. Epub 2010 Mar 4.

6. Cervero F, Laird JM. Visceral pain. Lancet. 1999 Jun 19;353(9170):2145-8.7. Backonja  M Defining neuropathic pain. Anesth Analg.2003;97:785-7908. Max  MB Clarifying the definition of neuropathic pain. Pain.2002;96:406-407.9. Grichnik KP, Ferrante FM. The difference between acute and chronic pain. Mt Sinai J

Med. 1991 May;58(3):217-20.10. Woolf CJ, Ma Q. Nociceptors—noxious stimulus detectors. Neuron. 2007;55(3):353–

36411. Abrahamsen B, et al. The cell and molecular basis of mechanical, cold, and

inflammatory pain. Science. 2008;321(5889):702–70512. Dubin, Adrienne and Patapoutian, Adrum. Nociceptors: the sensors of the pain pathway

J Clin Invest. 2010 Nov 1; 120(11): 3760–3772.

13. Todd, Andrew J. Neuronal circuitry for pain processing in the dorsal horn. Nature Reviews Neuroscience 11, 823-836 (December 2010)

14. Suzuki R, Dickenson A. Spinal and supraspinal contributions to central sensitization in peripheral neuropathy. Neurosignals. 2005;14(4):175-81.

15. Cross SA. Pathophysiology of Pain. Mayo Clin Proc. 1994;69:375–83.16. Monconduit L, Bourgeais L, Bernard JF, Le Bars D, Villanueva L. Ventromedial

thalamic neurons convey nociceptive signals from the whole body surface to the dorsolateral neocortex. J Neurosci. 1999;19

17. Craig AD, Dostrovsky JO. Medulla to thalamus. In: Wall PD, Melzack R, editors. Churchill-Livingstone; New York: pp. 183–214. textbook of pain.

18. Casey KL, Lorenz J, Minoshima S. Insights into the pathophysiology of neuropathic pain through functional brain imaging. Exp Neurol. 2003;184(Suppl 1):S80–8.

19. Shishir Ram Shetty, RL Anusha. Wallenberg’s syndrome. J Neurosci Rural Pract. 2012 Jan-Apr; 3(1): 100–102

20. Chudler, Eric. Dong, Willie. The role of the basal ganglia in nociception and pain. Pain. Jan 1995;60 (1): 3-38.

21. Gallez,Ariane Albanese, Marie-Claire, Rainville, Pierre, Duncan, Gary. Attenuation of Sensory and Affective Responses to Heat Pain: Evidence for Contralateral Mechanisms. Journal of Neurophysiology Published 1 November 2005; 94(5):3509-351

22. Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: The search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol. 1991;66:212–227

23. Baumgärtner U, Magerl W, Klein T, Hopf HC, Treede RD. Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain. Pain. 2002 Mar;96(1-2):141-51.

24. Aloisi, Anna. Bonifazi, Marco. Sex hormones, central nervous system and pain. Hormones of Behavior June 2006:50(1):1-7.

25. Herrero JF, Laird JM, López-García JA. Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol. 2000 Jun;61(2):169-203.

26. Latremolere, Adam. Woolf, Clifford. Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity. J Pain. 2009 Sep; 10(9): 895–926.

27. M. S. Bates, “Ethnicity and pain: a biocultural model,” Social Science and Medicine, vol. 24, no. 1, pp. 47–50, 1987.

28. L. Montes-Sandoval, “An analysis of the concept of pain,” Journal of Advanced

Nursing, vol. 29, no. 4, pp. 935–941, 1999.29. S. Nayak, S. C. Shiflett, S. Eshun, and F. M. Levine, “Culture and gender effects in pain

beliefs and the prediction of pain tolerance,” Cross-Cultural Research, vol. 34, no. 2, pp. 135–151, 2000.

30. K. F. Koltyn, “Analgesia following exercise: a review,” Sports Medicine, vol. 29, no. 2, pp. 85–98, 2000.

31. C. A. Ray and J. R. Carter, “Central modulation of exercise-induced muscle pain in humans,” Journal of Physiology, vol. 585, no. 1, pp. 287–294, 2007.

32. Y. Shi, T. N. Weingarten, C. B. Mantilla, W. M. Hooten, and D. O. Warner, “Smoking and pain: pathophysiology and clinical implications,” Anesthesiology, vol. 113, no. 4, pp. 977–992, 2010.

33. K. M. Woodrow and L. G. Eltherington, “Feeling no pain: alcohol as an analgesic,” Pain, vol. 32, no. 2, pp. 159–163, 1988.

34. M J Brownstein. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993 Jun 15; 90(12): 5391–5393.

35. Bozarth, M.A. Ventral tegmental reward system. Brain Reward Systems and Abuse (pp. 1-17). New York: Raven Press. (1987a).

36. Gallagher RM, Rosenthal LJ. Chronic pain and opiates: balancing pain control and risks in long-term opioid treatment. Arch Phys Med Rehabil 2008;89(3 Suppl 1):S77-82.

37. Chou R, Fanciullo GJ, Fine PG et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009; 10 (3): 113-130.

1

38. Ross JM, DeHoratius J. Non narcotic analgesics. In: DiPalma JR and DiGregorio GJ editors. Basic pharmacology in medicine. 3rd ed., McGraw hill publishing company New York, 1990. p. 311-316.

39. Olive G. Analgesic/Antipyretic treatment: ibuprofen or acetaminophen? An update. Therapies 2006. Mar-Apr;61(2).

40. Calrk WG, Brater DC, Jhonson AR. Non steroidal anti inflammatory, anti pyretic analgesics. In: Goth’s medical pharmacology. 13th ed., Mosby year book. St: Louis Baltimore Booston. 1992.

41. Barkin RL Acetaminophen, aspirin, or Ibuprofen in combination analgesic products. Am J Ther. 2001 Nov-Dec;8(6):433-42.

42. Vyvey,Melissa MD. Steroids as pain relief adjuvants. Can Fam Physician. 2010 Dec; 56(12): 1295–1297.

43. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409.

44. Dwokin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237-251.

45. Anthony H Dickenson, Anthony PhD. Rahman, Wahida PhD. Recent Developments in Neuropathic Pain Mechanisms: Implications for Treatment. British Journal of Pain June 2011 vol. 5 no. 2 21-25

46. Bernstein E, Carey TS, Garrett JM. The use of muscle relaxant medications in acute low back pain. Spine. 2004;29(12):1345–51.

47. Kobayashi H, Hasegawa Y, Ono H. Cyclobenzaprine, a centrally acting muscle relaxant, acts on descending serotonergic systems. Eur J Pharmacol. 1996;311(1):29–35

48. Lu Z, Xu J, Rossi GC, Majumdar S, Pasternak GW, Pan YX. Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J Clin Invest. 2015 Jul 1;125(7):2626-30.

49. Galanie, Stephanie. Thodey, Kate. Trenchard, Isis. Filsinger, Maria. Smolke, Christina. Complete biosynthesis of opioids in yeast. Science 4 September 2015: Vol. 349 no. 6252 pp. 1095-1100

50. Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry. 1978;35:501

51. Gowling L, Ali R, White J. Burprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2004;(4):CD002025.

52. Mendelson J, Upton RA, Everhart ET, Jacob P III, Jones RT. Bioavailability of sublingual buprenorphine. J Clin Pharmacol. 1997;37:31–7.

53.

54.

55.

56.

57.

58.

60.

1