Pain and nociception
|Pain and nociception|
Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
Pain (from Ancient Greek ποινή - poine) is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.
Pain in animals, including humans, is frequently the result of nociception; activity in the nervous system that results from the stimulation of nociceptors. This activity is carried to the brain, usually via the spinal cord, and conveys information, without conscious awareness, about damage or near-damage in body tissues. Pain is the conscious experience of sensorial information and a feeling of unpleasantness that can manifest as a result of nociception. Neuropathic pain differs from nociceptive pain in that it involves damage to the nerve resulting in the sensation of pain. There is also central pain in which the pain is generated in the brain from some form of lesion, and which is the most difficult for medical professionals to treat. Occasionally pain may be psychogenic, meaning caused by mental illness; however this is exceedingly rare.
As a part of the body's defense system, pain triggers mental and physical behavior that seek to end the painful experience. It is also a feedback system that promotes learning, making repetition of the painful situation less likely. The nociceptive system may transmit signals that trigger the sensation of pain, it is a critical component of the body's ability to react to damaging stimuli and it is part of a rapid-warning relay instructing diverse organs and principally the central nervous system to initiate reactions for minimizing injury.
Pain may range in intensity from slight through severe to agonizing and can appear as permanent or intermittent. It may be experienced as sharp, throbbing, dull, nauseating, burning, shooting or a combination of these. The threshold of pain might have wide variation between individuals. Pain may be quantified on a pain numeric rating scale (NRS) that ranges from 1-10 points; the accuracy of such as scale (using a cut point of 4 or more) for predicting pain that interferes with functioning is:
- sensitivity 64%
- specificity 83%
Localization is not always accurate in defining the problematic area. Some pain sensations may be diffuse or referred. Referred pain, usually happening in visceral disease, occurs when sensory fibres from the viscus enter the same segment of the spinal cord as somatic nerves i.e. those from superficial tissues. The sensory nerve from the viscus stimulates the closely associated nerve in the spinal cord and the pain perceived at the sensorial area of the brain is perceived as originating in the area supplied by the somatic nerve. An example is the left shoulder pain associated with heart damage.
This subjective localisation of pain to an area of the body defines some kind of pain as neck pain, cutaneous pain, kidney pain, or the painful uterine contractions occurring during childbirth. This common usage of pain is not entirely consistent with the scientists' model of pain being a subjective experience.
Nurses use the PQRST method to qualify the pain
P = provocation / palliation : what were you doing when the pain started? What caused it? What makes it better? worse? What seems to trigger it? Stress? Position? Certain activities? Arguments? Does it seem to be getting better, or getting worse, or does it remain the same? What relieves it: changing diet? changing position? taking medications? being active? resting? What makes (the problem) worse?
Q = quality / quantity : What does it feel like? Is it sharp? Dull? Stabbing? Burning? Crushing? throbbing? nauseating? shooting? twisting? stretching? Other? (The person who is suffering the pain should describe the pain, rather than saying what they think you would like to hear.) How does it feel, look or sound? How much of it is there?
R = region / radiation : Where is the pain located? Does the pain radiate (i.e. spread to another location, eg. pain source is from thumb but pain spreads to elbow)? Where does it radiate? Is it all in one place? Does it go anywhere else? Did it start elsewhere and now localised to one spot? Does it feel like it travels/moves around?
S = severity scale : How severe is the pain on a scale of 0 - 10, zero being no pain at all and 10 being the worst pain ever? Does it interfere with activities? How bad is it when it's at its worst? Does it force you to sit down, lie down, slow down? How long does an episode last?
T = timing : When did the pain start, at what time? How long did it last? How often does it occur? Is it sudden or gradual? What were you doing when you first experienced or noticed it? How often do you experience it: hourly? daily? weekly? monthly? When do you usually experience it: daytime? night? in the early morning? Are you ever awakened by it? Does it lead to anything else? Is it accompanied by other signs and symptoms? Does it ever occur before, during or after meals? Does it occur seasonally?
Other questions to ask when assessing a person in pain:
- Any medication or allergies?
- Does it hurt on deep inspiration?
- Activity at onset?
- Any history of pain?
- Is it the same?
- Any family history of heart disease, lung problems, diabetes, stroke, hypertension?
- Check LOC
- Midline trachea?
- Any recent trauma?
The purpose for these questions are to be as specific as possible in the description of the pain : when and where, what it feels like... The more specific and detailed information, the better it will be to diagnose the problem/cause and find a way to alleviate it.
Insensitivity to pain
Inability to experience pain, as in the rare condition congenital insensitivity to pain or congenital analgesia, is a cause of physical damage due to unawareness. Insensitivity to pain may also be caused by Hansen's disease or other forms of nerve damage.
CIP presents in early childhood with a child frequently getting injuries, such as broken bones and bruises, because they fail to develop the normal avoidance of pain and so take risks others would not.
While such conditions are extremely rare, they may present a picture of child abuse to the health care provider who frequently reports to child protection, the police, or other agencies.
Management and therapy of pain
Pain can be acute or chronic. The distinction between acute and chronic pain is not based on its duration of sensation, but rather the nature of the pain itself. Management and therapy is adequated to this distinction.
In general, physicians are more comfortable treating acute pain, which usually is caused by soft tissue damage, infection and/or inflammation among other causes. It is usually treated simultaneously with pharmaceuticals or appropriate techniques for removing the cause and pharmaceuticals or appropriate techniques for controlling the pain sensation, commonly analgesics. Acute pain serves to alert after an injury or malfunction of the body.
General physicians have only elementary training in chronic pain management and patients suffering from it are referred to specialists.
Chronic pain may have no apparent cause or may be caused by a developing illness or imbalance. This disorder can trigger multiple psychological problems that confound both patient and health care provider, leading to various differential diagnoses and to patient's feelings of helplessness and hopelessness. Sometimes chronic pain can have a psychosomatic or psychogenic cause.
Chronic pain was originally defined as pain that has lasted 6 months or longer. It is now defined as "the disease of pain." Its origin, duration, intensity, and specific symptoms vary. The one consistent fact of chronic pain is that, as a disorder, it cannot be understood in the same terms as acute pain.
The failure to treat acute pain properly may lead to chronic pain in some cases.
Hypnosis as well as diverse perceptional techniques provoking altered states of consciousness have proven to be of important help in the management of all types of pain. Some kinds of physical manipulation or exercise are showing interesting results as well.
Sources of pain
The experience of physiological pain can be grouped according to the source and related nociceptors (pain-detecting neurons).
- Cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. Examples of injuries that produce cutaneous pain include paper cuts, minor cuts, minor (first degree) burns and lacerations.
- Somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves. It is detected with somatic nociceptors. The scarcity of pain receptors in these areas produces a dull, poorly-localized pain of longer duration than cutaneous pain; examples include sprains and broken bones. Myofascial pain usually is caused by trigger points in muscles, tendons and fascia, and may be local or referred.
- Visceral pain originates from body's viscera, or organs. Visceral nociceptors are located within body organs and internal cavities. The even greater scarcity of nociceptors in these areas produces pain that is usually more aching and of a longer duration than somatic pain. Visceral pain is extremely difficult to localize, and several injuries to visceral tissue exhibit "referred" pain, where the sensation is localized to an area completely unrelated to the site of injury. Myocardial ischaemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm or even hand. The popularized term "brain freeze" is another example of referred pain, in which the vagus nerve is cooled by cold inside the throat. Referred pain can be explained by the findings that pain receptors in the viscera also excite spinal cord neurons that are excited by cutaneous tissue. Since the brain normally associates firing of these spinal cord neurons with stimulation of somatic tissues in skin or muscle, pain signals arising from the viscera are interpreted by the brain as originating from the skin. The theory that visceral and somatic pain receptors converge and form synapses on the same spinal cord pain-transmitting neurons is called "Ruch's Hypothesis".
- Phantom limb pain, a type of referred pain, is the sensation of pain from a limb that has been lost or from which a person no longer receives physical signals. It is an experience almost universally reported by amputees and quadriplegics.
- Neuropathic pain, can occur as a result of injury or disease to the nerve tissue itself. This can disrupt the ability of the sensory nerves to transmit correct information to the thalamus, and hence the brain interprets painful stimuli even though there is no obvious or known physiologic cause for the pain. Neuropathic pain is, as stated above, the disease of pain. It is not the sole definition for chronic pain, but does meet its criteria.
Some possible causes of pain by region
Note: Not a self-diagnosis guide
Visceral pain sensation is often referred by the CNS to a dermatome region which may be far away from the originating organ. These correlate to the position of the organ in the embryo. Examples of this include the heart which originates in the neck, thus producing the classical pain and arm pain experienced during acute cardiac pain.
Head and neck
- Jaw - Temporal arteritis (serious), trauma
- Ear - otitis media (very common esp. in children), otitis externa, trauma
- Eye - glaucoma, trauma
- Head - migraine, tension headache, cluster headache, cancer, cerebral aneurysm, sinusitis, meningitis
- Neck pain - MI (atypical), trauma
- Back - cancer, also see joints section
- Breast - perimenstrual, cancer, trauma
- Chest - MI (common and sometimes fatal), GERD (very common), pancreatitis, hiatal hernia, aortic dissection (rare), pulmonary embolism (more frequently asymptomatic), Costochondritis
- Shoulder - cholecystitis (right side), MSK
- Left and right upper quadrant - peptic ulcer disease, gastroenteritis, hepatitis, pancreatitis, cholecystitis, MI (atypical), abdominal aortic aneurysm, gastric cancer (usually asymptomatic)
- Left and right lower quadrant - appendicitis (serious), ulcerative colitis, crohn's disease, ectopic pregnancy (serious/women only), endometriosis (women only), pelvic inflammatory disease (women only), diverticulitis (common in the elderly), urolithiasis, pyelonephritis, cancer (colorectal cancer most common)
- Back - MSK (muscle strain), cancer, spinal disc herniation, degenerative disc disease, coccyx (coccydynia), also see joints section
- Arm - myocardial infarction (classically the left arm, sometimes bilateral), musculoskeletal
- Leg - deep vein thrombosis, peripheral vascular disease (claudication), musculoskeletal, spinal disc herniation, sciatica
- Classically small joints - osteoarthritis (common in the elderly), rheumatoid arthritis, systemic lupus erythematosis, gout, pseudogouttarsal/carpal tunnel syndrome
- Classically large joints (hip, knee) - osteoarthritis (common in the elderly), septic arthritis, hemarthrosis, osteonecrosis, trauma
- Classically back - ankylosing spondylitis, inflammatory bowel disease
- Other - psoriatic arthritis, Reiter's syndrome
Definitions of pain
Experts in pain have proposed a variety of definitions. These definitions illustrate the multi-faceted nature of pain.
"Pain is whatever the experiencing person says it is; existing whenever he or she says it does.”
"Pain is a category of complex experiences, not a single sensation produced by a single stimulus".
Physiology of nociception
Pain refers to the subjective, unpleasant sensation that accompanies damage or near-damage to tissues, though it can also occur in the absence of such damage if the systems of nociception are not functioning properly. Nociception refers to the system that carries signals of damage and pain from the tissues; it is the physiological event that accompanies pain.
All nociceptors are free nerve endings that have their cell bodies outside the spinal column in the dorsal root ganglion and are named based upon their appearance at their sensory ends. Nociceptors can detect mechanical, thermal, and chemical stimuli, and are found in the skin and on internal surfaces such as the periosteum or joint surfaces. Deep internal surfaces are only weakly supplied with pain receptors and will propagate sensations of chronic, aching pain if tissue damage in these areas occurs.
Nociceptors do not adapt to stimulus. In some conditions, excitation of pain fibers becomes greater as the pain stimulus continues, leading to a condition called hyperalgesia.
Transmission of nociception to the central nervous system
There are two ways for nociceptive information to reach the central nervous system, the neospinothalamic tract for 'fast spontaneous pain' and the paleospinothalamic tract for 'slow increasing pain'.
Fast pain travels via type Aδ fibers to terminate on the dorsal horn of the spinal cord where they synapse with the dendrites of the neospinothalamic tract. The axons of these neurons travel up the spine to the brain and cross the midline through the anterior white commissure, passing upwards in the contralateral anterolateral columns. These fibres terminate on the ventrobasal complex of the thalamus and synapse with the dendrites of the somatosensory cortex. Fast pain is felt within a tenth of a second of application of the pain stimulus and is a sharp, acute, prickling pain felt in response to mechanical and thermal stimulation. It can be localised easily if Aδ fibres are stimulated together with tactile receptors.
Slow pain is transmitted via slower type C fibers to laminae II and III of the dorsal horns, together known as the substantia gelatinosa. Impulses are then transmitted to nerve fibers that terminate in lamina V, also in the dorsal horn, synapsing with neurons that join fibers from the fast pathway, crossing to the opposite side via the anterior white commissure, and traveling upwards through the anterolateral pathway. These neurons terminate throughout in the brain stem, with one tenth of fibres stopping in the thalamus, and the rest stopping in the medulla, pons and periaqueductal grey of the midbrain tectum. Slow pain is stimulated by chemical stimulation, is poorly localized and is described as an aching, throbbing or burning pain.
Effects in CNS
When the nociceptors are stimulated they transmit signals through sensory neurons in the spinal cord. These neurons release the exicitory neurotransmitter glutamate at their synapses.
If the signals are sent to the reticular formation and thalamus, the sensation of pain enters consciousness in a dull poorly localised manner. From the thalamus, the signal can travel to the somatosensory cortex in the cerebrum, when the pain is experienced as localised and having more specific qualities.
Nociception can also cause generalized autonomic responses before or without reaching consciousness to cause pallor, diaphoresis, bradycardia, hypotension, lightheadedness, nausea and fainting.
The body possesses an endogenous analgesia system, which can be supplemented with analgesic drugs to regulate nociception and pain. There is both an analgesia system in the central nervous system and peripheral receptors that decreases the grade in which pain reaches the higher brain areas. The perception of pain can be modified by the body according to gate control theory of pain.
The central analgesia system is mediated by 3 major components : the periaquaductal grey matter, the nucleus raphe magnus and the nociception inhibitory neurons within the dorsal horns of the spinal cord, which act to inhibit nociception-transmitting neurons also located in the spinal dorsal horn.
The peripheral regulation consists of several different types of opioid receptors that are activated in response to the binding of the body's endorphins. These receptors, which exist in a variety of areas in the body, inhibit firing of neurons that would otherwise be stimulated to do so by nociceptors.
The gate control theory of pain, proposed by Patrick Wall and Ron Melzack, postulates that nociception (pain) is "gated" by non-nociception stimuli such as vibration. Thus, rubbing a bumped knee seems to relieve pain by preventing its transmission to the brain. Pain is also "gated" by signals that descend from the brain to the spinal cord to suppress (and in other cases enhance) incoming nociception (pain) information.
Phenotype and pain
Pain may be experienced differently depending on phenotype. A study by Liem et al. suggests that redheads are more susceptible to thermal pain.
Gene SCN9A has been identified as a major factor in the development of the pain-perception systems within the body. A rare genetic mutation in this area causes non-functional development of certain sodium channels in the nervous system, which prevents the brain from receiving messages of physical damage. People having this disorder are completely ignorant to pain, and can perform without pain any kinds of self mutilation or damage. In the families studied, this has ranged from biting of the person's own tongue leading to damage, through to street acts with knives, to death from injuries due to a failure to have learned limits on injury through experience of pain. The same gene also appears to mediate a form of hyper-sensitivity to pain, with other mutations seeming to be "at the root of paroxysmal extreme pain disorder" according to a 2006 report in Neurone. Various other forms of somatic sensitivity are unaffected.
Pain and alternative medicine
A recent survey by NCCAM (part of the NIH) found pain was the most common reason that people use alternative medicine. Among American adults who used CAM in 2002, 16.8% used CAM to treat back pain; 6.6% for neck pain; 4.9% for arthritis; 4.9% for joint pain; 3.1% for headache; and 2.4% used CAM to treat recurring pain. (Some survey respondents may have used CAM to treat more than one of these pain conditions.)
One such alternative, traditional Chinese medicine, views pain as a qi "blockage" equivalent to electrical resistance, or becoming chronic rather as "stagnation of blood" (Chinese: Xue) – theorized as dehydration inhibiting metabolism. Traditional Chinese treatments such as acupuncture are said to be more effective for nontraumatic pain than traumatic pain. Although these claims have not found broad scientific acceptance, research into both the mechanism and clinical efficacy of acupuncture supports that it can have a role in pain reduction for both humans and animals. Although the mechanism is not fully understood, it is likely that acupuncture stimulates the release of large quantities of endogenous opioids. A 2004 NCCAM-funded study showed that acupuncture provides pain relief and improved function in patients with osteoarthritis of the knee, causing some managed care organizations to support acupuncture as adjunctive therapy for this purpose. The NIH's 1997 Consensus Statement on Acupunture notes that research has been mixed, partly due to difficulties with designing clinical studies with the proper controls.
Another common alternative treatment for chronic pain is use of nutritional supplements such as:
- Curcumin, a polyphenol found in turmeric (Curcuma Longa) and said to be a natural cox-2 inhibitor
- Bromelain (a digestive enzyme from pineapple core)
- Omega-3 fatty acids.
The efficacy of Glucosamine and Chondroitin, popular supplements for patients with arthritis, were examinied in the GAIT study, a $12 million trial funded by the NIH which showed statistical evidence for the treatment's positive effect only amongst patients with moderate to severe pain, a small subsection of the study.
Philosophy of pain
The concept of pain has played an important part in the study of philosophy, particularly in the philosophy of mind. The question of what pain actually consists in is still open since any evaluation is dependent upon what subject one approaches the question from. Identity theorists assert that the mental state of pain is completely identical with some physical state caused by various physiological causes. Functionalists consider pain to be defined completely by its causal role (ie in the role it has in bringing about various effects) and nothing else. Some theologians and other spiritual traditions have much to say about the nature of pain and its various spiritual consequences, especially its role in growth, understanding, compassion, and in providing an aspect of life to be overcome.
Despite its unpleasantness, pain is an important part of the existence of humans and other animals; in fact, it is vital to survival. Pain encourages an organism to disengage from the noxious stimulus associated with the pain. Preliminary pain can serve to indicate that an injury is imminent, such as the ache from a soon-to-be-broken bone. Pain may also promote the healing process, since most organisms will protect an injured region in order to avoid further pain. People born with congenital insensitivity to pain usually have short life spans, and suffer numerous ailments such as broken bones, bed sores, and chronic infection.
The study of pain has in recent years diverged into many different fields from pharmacology to psychology and neurobiology. It is also a separate sub-discipline in some terminal illnesses specializations.
Interestingly, the brain itself is devoid of nociceptive tissue, and hence cannot experience pain. Thus, a headache is not due to stimulation of pain fibers in the brain itself. Rather, the membrane surrounding the brain and spinal cord, called the dura mater, is innervated with pain receptors, and stimulation of these dural nociceptors (pain receptors) is thought to be involved to some extent in producing headache pain, been the vasoconstriction of peripheral vessels another common cause. Some evolutionary biologists have speculated that this lack of nociceptive tissue in the brain might be because any injury of sufficient magnitude to cause pain in the brain has a sufficiently high probability of being fatal that development of nociceptive tissue therein would have little to no survival benefit.
Chronic pain, in which the pain becomes pathological rather than beneficial, may be an exception to the idea that pain is helpful to survival, although some specialists believe that psychogenic chronic pain exists as a protective distraction to keep dangerous repressed emotions such as anger or rage unconscious. It is not clear what the survival benefit of some extreme forms of pain (e.g. toothache) might be; and the intensity of some forms of pain (for example as a result of injury to fingernails or toenails) seem to be out of all proportion to any survival benefits.
Pain and nociception in other species
Pain is defined as a subjective conscious experience. The presence or absence of pain even in another human is only verifiable by their report; "Pain is whatever the experiencing person says it is, and exists whenever he says it does." Currently, it is not scientifically possible to prove whether an animal is in pain or not, however it can be inferred through physical and behavioral reactions.
In veterinary science all uncertainty is overcome by assuming that if something would be painful for a human then it would be painful for an animal. Where possible, analgesics are used preemptively if there is any likelihood of pain being caused to an animal.
- ↑ IASP Pain Terminology
- ↑ Krebs, Carey, and Weinberger, “Accuracy of the Pain Numeric Rating Scale as a Screening Test in Primary Care,” Journal of General Internal Medicine 22, no. 10 (October 21, 2007): 1453-1458, doi:10.1007/s11606-007-0321-2 (accessed September 28, 2007).
- ↑ Ann Waugh, Allison Grant (2001). Anatomy and Physiology in Health and Illness. Edinburgh: Churchill Livingstone. pp. pp 174-175. ISBN 0443-06468 7.
- ↑ 4.0 4.1 Sarno, John E., MD, et al., The Divided Mind: The Epidemic of Mindbody Disorders 2006 (ISBN 0-06-085178-3)
- ↑ Dahl JB, Moiniche S (2004). "Pre-emptive analgesia". Br Med Bull. 71: 13–27. PMID 15596866.
- ↑ Robert Ornstein PhD, David Sobel MD (1988). The Healing Brain. New York: Simon & Schuster Inc. pp. pp 98-99. ISBN 0-671-66236-8.
- ↑ Douglas E DeGood, Donald C Manning MD, Susan J Middaugh (1997). The headache & Neck Pain Workbook. Oakland, California: New Harbinger Publications. ISBN 1-57224-086-5.
- ↑ McCaffery M., Nursing management of the patient in pain. Philadelphia, Pa: Lippincott 1972.
- ↑ Melzack R, Wall PD. The Challenge of Pain. Penguin: Harmondsworth, 1982
- ↑ "Assessing Pain and Distress: A Veterinary Behaviorist's Perspective by Kathryn Bayne" in "Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000)
- ↑ cite seen at Feinstein B, J Langton, R Jameson, F Schiller. Experiments on pain referred from deep somatic tissues. J Bone Joint Surg 1954;36-A(5):981-97 retrieved 2007-01-06
- ↑ Liem EB, Joiner TV, Tsueda K, Sessler DI. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology. 2005 Mar;102(3):509-14.
- ↑ Access : The mutation that takes away pain : Nature News
- ↑ Robert Sapolsky, Why zebras don't get ulcers, pp 196-197: "Scientists noted that Chinese veterinarians used acupuncture to do surgery on animals, thereby refuting the argument that the painkilling characteristics of acupuncture was one big placebo effect ascribable to cultural conditioning (no cow on earth will go along with unanaesthetized surgery just because it has a heavy investment in the cultural mores of the society in which it dwells. [...] Acupuncture stimulates the release of large quantities of endogenous opioids, for reasons no one really understands. The best demonstration of this is what is called a subtraction experiment: block the activity of endogenous opioids by using a drug that blocks the opiate receptor... acupuncture no longer effectively dulls the perception of pain."
- ↑ Berman BM, Lao L, Langenberg P, Lee WL, Gilpin AM, Hochberg MC. "Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial." Annals of Internal Medicine 2004 Dec 21; 141(12): 901-10.
- ↑ National Institutes of Health Consensus Panel. "Acupuncture: National Institutes of Health Consensus Development Statement." National Institutes of Health Web site. Accessed at consensus.nih.gov/1997/1997Acupuncture107html.htm on February 24, 2007.
- ↑ Sharma S, Kulkarni SK, Agrewala JN, Chopra K. "Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain." Eur J Pharmacol. 2006 May 1; 536(3): 256-61
- ↑ Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, Bradley JD, Bingham CO, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher HR, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. "Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis." New England Journal of Medicine. 2006 Feb 23; 354(8): 795-808.
- ↑ cite sourced from McCaffery M. Nursing management of the patient in pain. Philadelphia, Pa: JB Lippincott 1972.
- ↑ American College of Veterinary Anesthesiologists' position paper on the treatment of pain in animals retrieved 2007-01-06
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