IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE)

Acupuncture and Pain Management

James D. Kenney, DVM

There is a large and expanding body of scientific evidence supporting the use of acupuncture in pain management. In the last decade, our understanding of how the brain processes acupuncture anal- gesia has undergone considerable development. Profound studies on neural mechanisms underlying acupuncture analgesia have evolved rapidly and predominately focus on cellular and molecular substrate and functional brain imaging. The currently understood mechanisms of acupuncture analgesia are complex and involve direct and indirect neurohumoral effects that block pain percep- tion, reduce the pain response, relieve muscle spasms, and reduce inflammation. The mechanisms of acupuncture involve the , hypothalamic-pituitary axis, mid- brain periaqueductal grey matter, medulla oblongata, , , and autonomic nervous system. Electroacupuncture (EA) stimulation of these sites results in activation of descend- ing pathways that inhibit pain through endogenous opioid, noradrenergic, and serotonergic sys- tems. There are growing numbers of human trials supporting the use of acupuncture as an evidence- based practice for pain management in human medicine. There are many studies that support the efficacy of acupuncture for low back pain, neck pain, chronic idiopathic and migraine headaches, knee pain, shoulder pain, fibromyalgia, temporomandibular joint pain, and postoperative pain. Although the number of well-designed, controlled clinical research studies in veterinary medicine is lagging behind the number of studies in human medicine, much of the basic science research has been done in animals with neurophysiology that is more similar to veterinary patients than humans. Although there is research to support EA as an evidence-based practice for the control of back pain in horses, additional studies are needed in other clinical situations in veterinary medicine where pain manage- ment is required. Author’s address: PO Box 717, Clarksburg, NJ 08510-0717; e-mail: jdkenneydvm@ msn.com. © 2011 AAEP.

1. Introduction provide relief from low back pain, neck pain, chronic According to the World Health Organization (WHO), idiopathic or tension headaches, migraine head- the effectiveness of acupuncture analgesia has been aches, knee pain, shoulder pain, fibromyalgia, tem- 2 established in controlled clinical trials, and the use peromandibular joint pain, and postoperative pain. of acupuncture to control chronic pain is comparable Acupuncture was more effective for chronic pain with morphine without the risk of drug dependence than placebos (sham acupuncture) based on the re- and other adverse side effects.1 Acupuncture is an sults of systematic reviews of pooled data from high- effective treatment for many types of pain, is well- quality randomized controlled trials.1,3 For short- tolerated by patients, and has a minimal likelihood term outcomes (less than 6 mo), acupuncture was of serious adverse effects.1–3 Modern and tradi- significantly superior to sham treatments for back tional acupuncture techniques have been shown to pain, knee pain, and headache. For longer-term

NOTES

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Table 1. Definitions of Terms

Term Definition

Neuropathic pain Pain from damage to the nervous system Nociceptive pain Pain from stimulation of nociceptors Peripheral endings in the skin, muscles, ligaments, joints, viscera, and Nociceptors other structures that initially respond to a painful stimulus Pain sense Mechanical, thermal, or chemical stimulus that alters nociceptors and causes Noxious pain Analgesia Reduced sensitivity to painful stimuli Anti-nociception Analgesia Internuncial neuron Neuron interposed between and connecting two other neurons Inhibit receptors on neurons; examples are serotonin, GABA, Inhibitory norepinephrine, and epinephrine Excitatory neurotransmitters Activate receptors on neurons; examples are glutamate and aspartate Periaqueductal grey matter that surrounds the cerebral aqueduct in the PAG midbrain Hyperalgesia Increased sensitivity to pain Allodynia Non-noxious stimuli perceived as painful Primary hyperalgesia Hypersensitivity of the peripheral nociceptors Central sensitization and hypersensitivity of CNS neurons associated with Secondary hyperalgesia synaptic plasticity Ability of the connection or synapse between two neurons to change in Synaptic plasticity strength and responsiveness Endogenous opioid polypeptide neurotransmitters that inhibit pain stimuli similar to morphine; includes ␤-endorphins, enkephalins, dynorphins, Endorphins endomorphin-1, and endomorphin-2 Neurons with cell bodies in the spinal cord whose axons form peripheral Lower motor neurons motor and terminate in skeletal, cardiac, and smooth muscles

outcomes (6–12 mo), acupuncture was significantly may not be as effective as corticosteroids for pain more effective for knee pain and tension-type head- relief in some patients with rheumatoid arthritis, ache but inconsistent for back pain (one meta-anal- but chronic corticosteroid use may result in gastro- ysis was positive and one meta-analysis was intestinal ulceration, osteopenia, muscle loss, and inconclusive). other adverse effects. Acupuncture not only re- Acupuncture can effectively treat chronic pain of duces pain and inflammation but has positive effects the locomotor system with restricted movements of on the immune system, which directly benefits pa- the joints, because it not only alleviates pain but tients with rheumatoid arthritis, and less conven- also reduces the muscle spasm that causes reduced tional medication may be needed.1 mobility.4,5 Muscle spasm can result in abnormal loads placed on joints, often causing clinical signs of 2. Pain Pathways and Modulation pain before changes are demonstrable on radio- Pain may be classified as acute or chronic, adaptive graphs. In controlled studies of joint pain of un- or maladaptive, and neuropathic or nociceptive, and known etiology, acupuncture was superior to these types of pain have different underlying mech- conventional therapy, delayed-treatment controls, anisms.2 Neuropathic pain occurs from damage to and several other sham acupuncture techniques. the peripheral or central nervous system (PNS or According to the WHO analysis of controlled studies, CNS, respectively). Pain associated with activa- acupuncture can effectively reduce pain from cervi- tion of sensory (afferent) receptors (nociceptors) by cal spondylitis and other causes of neck pain, peri- mechanical, thermal, or chemical stimuli is consid- arthritis of the shoulder, fibromyalgia, fasciitis, ered nociceptive pain and will primarily be reviewed epicondylitis, low back conditions, sciatica, osteoar- here. The pathways involved in nociceptive pain thritis, and radicular and pseudoradicular pain syn- are also involved with the modulation of pain by dromes.1 In some cases, acupuncture integrated acupuncture. Understanding PNS and CNS pain with conventional treatments was more effective pathways is essential to understanding acupuncture than conventional treatments alone. analgesia.6 Terms associated with pain and pain Although acupuncture may not reduce pain to the modulation are defined in Table 1. degree that some conventional treatments reduce Nociception (the sensation of pain) is extremely pain, it is associated with a low incidence of serious complex and involves more than simple transmis- adverse side effects.1 For example, acupuncture sion of pain signals from nociceptors of the PNS to

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Fig. 1. The basic three neuron pathways of pain (blue, first-order neurons; red, second-order neurons; green, third-order neurons) of the neo-spinothalmic system and the multisynaptic pathways of the paleo-spinoreticulo-diencephalic system and the bilateral spinothalamic system common in non-primate animals (black broken lines).

regions of the CNS for conscious perception. Pain of somatic and visceral first-order afferent nerves. signals are modified by substances released from When a specific threshold of excitation is reached, cells at the site of pain, within the spinal cord grey electrical action potentials transmit along their pe- matter, and by the concomitant stimulation of CNS ripheral processes to cell bodies in the dorsal root inhibitory descending pathways from higher brain ganglia and then into the spinal cord, where they centers. The main neuroanatomic structures in- synapse on second-order neurons in the dorsal horn volved in the complex process of pain perception grey matter. Stimulated second-order neurons include the peripheral sensory receptors (nocicep- propagate electrical signals along their axons, form- tors), afferent peripheral nerve fibers, dorsal horns ing ascending tracts in the spinal cord and brains- of the spinal cord (body) or sensory nucleus of the tem that synapse on third-order neurons in the trigeminal nerve (head), ascending pathways to the and other brain stem structures. The ac- in the medulla oblongata and tivated third-order neurons propagate electrical sig- midbrain, thalamus, , limbic system, nals along their axons that terminate in the and cerebral cortex as well as descending CNS path- somatosensory cortex of the cerebrum as well as ways from all these sites.6,7 other regions of the brain, where conscious percep- Ascending Pathways tion and evaluation of pain occur (Fig. 1). Con- From a simplified functional neuroanatomic stand- scious perception of pain may occur at both thalamic 7 point, the most direct pain pathways, like other sen- and cortical levels in animals. sory systems, can be basically viewed as a three For nociception from the head, electrical impulses neuron system: first-order, second-order, and of first-order neurons ascend in the trigeminal nerve third-order neurons (Fig. 1).7 Noxious (painful) (cranial nerve V) to cell bodies in the trigeminal mechanical, thermal, or chemical stimuli are de- ganglia and continue on to enter the and tected by nociceptors (primarily free nerve endings) synapse with second-order neurons in the trigemi-

AAEP PROCEEDINGS ր Vol. 57 ր 2011 123 IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) nal sensory nuclei in the medulla oblongata, pons, and midbrain (Fig. 1).6,7 The second-order neu- rons, from the trigeminal sensory nuclei, ascend the brainstem to synapse with third-order neurons in

the thalamus and other brainstem regions similar to site second-order neurons from the body and viscera. The first-order neurons that transmit pain and Termination II VII (T1-L1) VII (T1-L1) and V SC Laminae I and other sensations are classified according to their Medulla diameter, speed of conduction, function, and degree of myelination (Table 2).6 There are two classifica- tions for these fibers, numerical and alphabetical, which can be confusing when reading the literature. The alphabetical Erlinger-Gasser classification will be used throughout this review. The A␦ andCfi- Ascending

bers primarily conduct signals from nociceptive tract system ␦ thalamci stimuli. A fibers are myelinated, are rapidly con- (dorsal columns)

ducting, and mainly sense pain from the skin, and C Neo-spino-thalamic SC Laminae I, II, fibers are unmyelinated, are slowly conducting, and sense pain from skin, bone, viscera, and other struc- tures (Table 2). If A␦ and C fibers are stimulated simultaneously, the pain experienced will come in two phases. The first phase will be sharp and lo- calized and may be of short duration, because it is mediated by the faster-conducting A␦ fibers. The later phase is from the smaller and slower-conduct- ing C fibers, and it will be dull and non-localized but last longer. The second-order neuron cell bodies are located in temperature one or more physiologically distinct layers (laminae) and touch Gracilus and cuneatus of the spinal cord dorsal horn grey matter (Table 2).6,7 There are six laminae in the dorsal horn (I- VI), three in the ventral horn (VII-IX), and an addi- tional column of cells clustered around the as Lamina X. The C fibers terminate mainly in Laminae I and II, where their axons secrete Sub- stance P or Vasoactive Intestinal Polypeptide de- pending on whether they arise from somatic or visceral structures, respectively. The A␦ afferents terminate primarily in Laminae I, II, and V. Axons of the second-order neurons of the spinal cutaneous mechanoreceptors cord grey matter form two main ascending pathway systems that carry nociception: the neo-spinotha- lamic pathway system and the paleo-spino-reticulo- diencephalic pathway system (Fig. 1 and Table 3).4,6–8 In Laminae I and V, where the majority of Conduction A␦ nerves terminate, second-order neurons immedi- velocity (m/s) Receptors Sensation ately cross to the opposite side and form the neo- system in the anterolateral

portion of the spinal cord. These neurons termi- m) ␮ nate on third-order neuron cell bodies in the ventral ( posterior lateral (VPL) nucleus of the thalamus and Diameter project to the somatosensory cortex (Fig. 1 and Table 3). The neo-spinothalamic system is direct, fast, )) 12–20) 13–20 80–120 6–12 80–120 Muscle spindles Golgi 35–75 tendon organ Muscle spindles and all Proprioception Proprioception Spino-cerebellar Spino-cerebellar Medulla SC Lamina Medulla SC Lamina ) 1–5 3–30 Free nerve endings Touch, pain, and

␦ ␣ ␣ ␤

and localizing and is the basic three-neuron system ( ( ( (

␦ of discriminative pain. ␣ ␣ ␤ The paleo-spino-reticulo-diencephalic pathways system primarily originate from neurons in Laminae VII Erlanger-Gasser and VIII in the ventral horn of the spinal cord grey matter, with some input from Lamina V, and they

connect to C fibers that terminate in Laminae I and type Medulla, medulla oblongata. *Unmyelinated; all other types have some . Fiber Ia A IbII A IV* A C* 0.2–1.5 0.5–2.0 Free nerve endings Pain and temperature Paleo-spino-reticulo- III A

II through internuncial neurons (Fig. 1 and Table Table 2. Sensory Peripheral Nerve Types and Their Function

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Table 3. Comparison of the Two Main Central Pain Pathway Systems

Neo-Spinothalamic System Paleo-Spino-Reticulo-Diencephalic System

Origination Laminae I, IV, and V (stimulated by A␦ Laminae I, IV, and V (stimulated by C neurons) neurons) connect through internuncial neurons to Laminae VII and VIII Transmission Direct fast Indirect slow speed Subcortical targets None Reticular formation, hypothalamus, and limbic system Thalamic nuclei Ventral posterior lateral Intralaminar nuclei and other midline nuclei Cerebral cortex Parietal lobe (primary somatosensory cortex) Cingulate gyrus, prefrontal cortex, and frontal lobe Pain type Sharp pain, discriminative pain, and pin-prick Dull pain, affective arousal components of pain, and pain tissue-damage pain

2).4,6–8 Most axons from neurons in Laminae VII lus projected to the frontal cortex is interpreted and VIII cross to the opposite side in primates and along with past experiences, mood, and current cir- form their pathways in the anterolateral portion of cumstances, and this combination influences the the spinal cord adjacent to the neo-spinothalamic pain experience. pathways. They pass medially into the reticular formation (central core) of the brain stem and the Pain Modulation medial intralaminar nuclei of the thalamus, and The normal neurophysiology of pain modulation is then, they project to the cingulate gyrus and frontal also important to review to better understand poten- cortex (Table 2).8 tial sites of acupuncture pain control.6 When a In non-primates, some second-order neurons cross noxious stimulus is experienced, endogenous net- and others remain on the same side to form crossed works are activated that modulate pain at the pe- and uncrossed spinothalamic pathways.6,7 The ripheral nociceptors within tissues, in the dorsal spinothalamic pathways in animals are interrupted horn grey matter of the spinal cord, in the network by axons exiting and reentering after synapsing of relay stations between the dorsal horn and the with other spinal cord neurons, forming diffuse, cerebral cortex, and within the cerebral cortex (Fig. bilaterally represented multisynaptic pathways. 2).4,6–8 Some second-order nociceptive neurons may also as- The first-order afferent fibers not only connect to cend to the thalamus and other brainstem regions second-order neurons for the ascending pain path- through the dorsal column medial-lemniscal system, ways but also send off branches that synapse with which mainly transmits proprioceptive information inhibitory internuncial neurons in the spinal cord as well through multifunctional spinoreticular grey matter.4,6–8 Considerable modulation of pain tracts and the fasciculus proprius.7 occurs at the dorsal horn grey matter, where inhib- The reticular formation (central core of the me- itory internuncial neurons secrete ␥-aminobutyric dulla oblongata, pons, and midbrain) contains bifur- acid (GABA) and other neurotransmitters that in- cating axons that project up through the paleo- hibit C fibers and reduce activation of second-order spino-reticular-diencephalic pathways to the spinal cord nociceptive neurons. Larger-diameter diencephalon (thalamus and hypothalamus) and afferent nerves, like A␤ and A␦ fibers, terminate on down through reticulospinal tracts to the spinal cord inhibitory internuncial neurons in the dorsal horn to influence muscle tone. Axons from the reticular grey matter, which in turn, inhibit the nociceptive C formation that terminate in the hypothalamus also fibers and reduce the amount of re- synapse with autonomic neurons, which descend to leased (Fig. 2).4,6,8 the medulla oblongata and spinal cord to affect au- The ascending pathways of second-order nocicep- tonomic lower motor neurons and alter vascular tive neurons give off branches that synapse with tone, heart rate, gastrointestinal function, and other neurons at several sites in the brainstem that form visceral functions.4,6–8 Consequently, pain may descending pathways that inhibit pain. Neurons in cause autonomic signs of increased heart and respi- the midbrain periaqueductal grey matter (PAG) ratory rates, vasoconstriction, nausea, and send descending projections to the rostral ventrome- vomiting. dial medulla and spinal cord dorsal horn, which Part of what makes the pain experience so com- form the primary neuroanatomical pathways medi- plex and varied between individuals is the interpre- ating opioid-based analgesia (Fig. 2).4,6,8–10 Endor- tation of pain by higher brain centers. The limbic phins (␤-endorphin, enkephalin, and dynorphin) are system, which includes the hypothalamus, hip- neurotransmitters released by neurons in response pocampus, , and cingulate gyrus, is to painful stimuli and used internally to reduce thought to control the motivational, behavioral, and pain. ␤-Endorphin is found primarily in the pitu- emotional responses to pain.4,6–8 The pain stimu- itary gland, but enkephalin and dynorphin are pro-

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Fig. 2. Three main regions for normal pain modulation and sites of EA pain suppression. (1) Spinal cord dorsal horn. Some of the painful stimuli from C fibers (blue) are blocked (black bar) by impulses from the A␤ and A␦ fibers (purple) stimulated by EA and pain, which arrive first and compete for sites on the second-order neurons in the spinal cord dorsal horn grey matter. In addition, branches of the A␦ fibers stimulate spinal cord internuncial neurons that release enkephalin, dynorphin, GABA, and other inhibitory substances. (2) Descending endogenous opioid pathways. Neurons in the diencephalon, midbrain PAG, and medulla oblongata (stimulated by ascending pain pathways and EA) release endorphins through descending pathways to the spinal cord grey matter to block ascending pain impulses (red line represents the primary pathways mediating opioid-based analgesia) as well as into the blood through the pituitary. (3) Descending seratonergic and noradrenergic inhibitory pathways. Neurons in the cerebrum, diencephalon, midbrain, pons, and medulla (stimulated by ascending pain pathways and EA) release serotonin, norepineprine, and other inhibitory neurotransmitters through descending pathways to the spinal cord grey matter to block ascending pain impulses (green line represents the primary seratonergic pathways).

duced throughout the nervous system, including the hibits pain transmission, leading to a decrease in dorsal grey matter of the brainstem and spinal cord. perceived pain. Descending pathways from the Enkephalinergic internuncial neurons are located midbrain PAG and locus coeruleus and raphe nuclei on the border of Laminae I and II of the spinal cord of the medulla oblongata are inhibitory to dorsal grey matter and alter the responses of second-order grey column nerves of the spinal cord, and some of nociceptive neurons located there. Endorphins in- the inhibition is mediated by serotonin (Fig. teract with opioid receptors on neurons to reduce the 2).6,7,9,10 The pain suppressing effect of antidepres- intensity of pain. Opioid receptors are found in sants is probably because of their ability to enhance many areas of the brain, but they are especially transmission down these pathways by blocking the concentrated in the PAG and dorsal horns of the uptake of 5HT. spinal cord. Serotoninergic descending inhibitory pathways Pathological Pain States are also suggested to be an important mechanism of The peripheral terminals of C fibers become sensi- analgesia (antinociception). Serotonin (5-hydroxy tized during tissue damage and subsequent inflam- tryptophan [5HT]) is a , which in- mation by the release of bradykinin, serotonin,

126 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) potassium, adenosine 5Ј-triphosphate (ATP), prosta- or kissing spine conditions in the equine and other glandins, and leukotrienes from damaged tissue and species. inflammatory cells. These sensitized C fibers se- Neuropathic pain is also common in humans and crete Substance P (a ) and calcitonin animals. Inflammation and primary damage to gene-related peptide, which have a vasodilatory ef- nerves alter their normal response to stimulation fect on local blood vessels and stimulate additional and modulation and can cause muscle spasm and release of inflammatory mediators, further sensitiz- shortening, which also amplify the ing the peripheral nociceptors.4,8 Sensitization pain.4,5,11 Nerve root inflammation from spondylo- lowers the threshold for activation, increases the sis, intervertebral disk protrusion and other degen- magnitude and duration of activation, and results in erative vertebral column changes causes spasm and peripheral (primary) hyperalgesia and allodynia shortening of paravertebral muscles that compress (non-noxious stimuli being perceived as painful). intervertebral discs and create a self-perpetuating If there is massive or prolonged stimulation of C cycle of contraction, inflammation, radiculopathy, 11 fibers, there is activation of N-methyl-D-aspartate and pain. (NMDA) receptors, which reduces the receptor 3. Mechanisms of Acupuncture Pain Control threshold for activation of the dorsal horn neurons and spontaneous depolarization. This activation Acupuncture is the stimulation of specific pre-deter- results in increased pain impulses ascending to mined points (acupoints) near the surface of the higher levels in the brain.4,6 Chronic pain stimu- body, which produces a therapeutic effect by evoking lation not only causes local and spinal cord hyper- homeostatic mechanisms within the nervous, im- mune, endocrine, cardiovascular, and other body sensitivity to pain but also increases sensitivity 6,8–12 through its effects on higher synaptic sites in the systems to promote self-healing. Acupunc- brainstem and cerebrum. These changes are a type ture stimulates small nerve endings and other struc- of synaptic plasticity and central (secondary) hyper- tures around the acupoints, which result, in both algesia and allodynia result.4,11 local and distant changes within the body. Ancient Chronic pain, as distinct from acute pain, distin- traditional Chinese medical theories have explained the effects of acupuncture based on empirical obser- guishes itself by its persistence in the absence of vations and descriptions of naturally occurring phe- inflammation or other obvious ongoing tissue-dam- nomena, and the underlying complex neurochemical aging processes, delay in onset after the precipitat- mechanisms behind their observations have been ing injury, and abnormal or unpleasant sensations explored in scientific studies for the past 50 yr.13 such as burning, searing, or deep, aching pain un- Our understanding of how the brain processes responsive to conventional anti-inflammatory 11 acupuncture analgesia has undergone considerable drugs. Persistent pain and sensitization can of- development.14 Acupuncture analgesia is mani- ten lead to additional loss of function from reduced fested only when the intricate feeling (soreness, range of motion in joints and the mechanical effects numbness, heaviness, and distension) of acupunc- of muscle shortening. Prolonged limitations of ture in patients occurs after acupuncture manipula- movement can result in disuse atrophy of muscles, tion. Manual acupuncture (MA) is the insertion of which also limits mobility. an acupuncture needle into an acupoint followed by Pain not only originates from cutaneous struc- the twisting of the needle up and down by hand. tures but also arises from nociceptive receptors in ␤ ␦ 4,5 In MA, all types of afferent fibers (A ,A , and C) are muscles, tendons, and joints. Focal acute pain activated. In electrical acupuncture (EA), a stimu- may be associated with muscle spasm and lactic acid lating current through the inserted needle is deliv- accumulation and may result in muscle shorten- 11 ered to acupoints. Electrical current intense ing. A major consequence of muscle shortening is enough to excite A␤ and part of A␦ fibers can induce the continuous, unremitting pull on the structures an analgesic effect. Acupuncture signals ascend to which the muscle attaches. mainly through the spinal ventrolateral funiculus to that spans a joint can create pressure within the the brain. Many brain nuclei composing a compli- joint, abnormal patterns of motion, arthralgia (joint cated network are involved in processing acupunc- pain), injury, and finally, degenerative joint disease. ture analgesia, including the nucleus raphe magnus The presence of muscle shortening also has delete- (NRM), PAG, locus coeruleus, arcuate nucleus (Arc), rious effects on the tendons and ligaments. Unre- pre-optic area, nucleus submedius, habenular nu- lenting muscle tension on these structures may be cleus, accumbens nucleus, caudate nucleus, septal the precipitating factor in bicipital bursitis, epicon- area, amygdale, etc. Acupuncture analgesia is es- dylitis, hock and stifle degeneration, upper suspen- sentially a manifestation of integrative processes at sory pain, chondromalacia of the stifle joint, and different levels in the CNS between afferent im- other pathologic conditions that are frequently seen pulses from pain regions and impulses from acu- in veterinary practice. Continuous pressure on points. In the last decade, profound studies on vertebral joint surfaces from muscle contractions neural mechanisms underlying acupuncture analge- causes vertebral facet degeneration, which may be a sia predominately focus on cellular and molecular key factor in interspinal osteoarthrosis (spondylosis) substrate and functional brain imaging and have

AAEP PROCEEDINGS ր Vol. 57 ր 2011 127 IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) developed rapidly. Diverse signal molecules con- Analgesic effects of EA have been shown to occur tribute to mediating acupuncture analgesia, such as in the spinal cord grey matter, hypothalamic-pitu- opioid peptides (␮-, ␦-, and ␬-receptors), glutamate itary axis, midbrain PAG, pons, medulla oblongata, (NMDA and AMPA/KA receptors), 5HT, and chole- limbic system, cerebral cortex, and autonomic ner- cystokinin octapeptide (CCK-8). Among these mol- vous system (Fig. 2). Changes in EA stimulation ecules, the opioid peptides and their receptors in the frequency can alter the site of antinociceptive activ- Arc-PAG-NRM-spinal dorsal horn pathway play a ities, and the antinociceptive effects of EA in normal pivotal role in mediating acupuncture analgesia. and hypersensitized painful humans and animals The release of opioid peptides evoked by electroacu- can be quite different.6,13 A striking feature of acu- puncture is frequency-dependent. EA at 2 and 100 puncture-induced analgesia is its long-lasting effect, Hz produces, respectively, releases of enkephalin which has a delayed onset and gradually reaches a and dynorphin in the spinal cord. CCK-8 antago- peak even after acupuncture needling is terminated. nizes acupuncture analgesia. The individual dif- A non-repeated, event-related (NRER) fMRI para- ferences of acupuncture analgesia are associated digm and control theory-based approach was ad- with inherited genetic factors and the density of opted to capture the detailed temporal profile of 21 CCK receptors. The brain regions associated with neural responses induced by acupuncture. Neu- acupuncture analgesia identified in animal experi- ral activities at the different stages of acupuncture ments were confirmed and further explored in the presented distinct temporal patterns in which con- human brain by means of functional imag- sistently positive neural responses were found dur- ing. There are still many unanswered questions ing the period of acupuncture needling, whereas concerning the mechanisms of acupuncture analge- much more complex and dynamic activities were sia, but there is no doubt that acupuncture produces found during a post-acupuncture period. The effects at many different sites that result in amygdala and perigenual anterior cingulate cortex analgesia.9,10,12,13 (pACC), exhibited increased activities during the The analgesic effects of EA on brain function can needling phase, which decreased gradually to reach be visualized using functional magnetic resonance a peak below the baseline. The PAG and hypothal- amus presented saliently intermittent activations imaging (fMRI) and positron emission tomography across the whole fMRI session. The overall find- (PET) scans.9 With a painful stimulus, the fMRI ings indicate that acupuncture may engage differen- shows activation of areas in the cingulate cortex, tial temporal neural responses as a function of time thalamus, and other regions of the brain, but there in a wide range of brain networks. is a significant decrease of activation in these areas A relatively new analysis method, functional con- after acupuncture. This finding suggests that acu- 9 nectivity fMRI (fcMRI), has great potential for puncture desensitizes or blocks pain at these levels. studying continuous treatment modalities such as This finding may be associated with acupuncture EA. Compared with sham acupuncture, EA can modulation of pain at the dorsal horn grey matter significantly reduce PAG activity when subse- and a reduction of ascending impulses along the quently evoked by experimental pain. Findings in- spinothalamic pathway systems, or it may be asso- dicate the intrinsic functional connectivity changes ciated with neurochemical alterations higher in the among key brain regions in the pain matrix and brainstem. default mode network during genuine EA compared The currently understood mechanisms of acu- with sham EA.22 puncture pain control are complex and involve direct One of the earliest proposed mechanisms of EA and indirect neurochemical effects that block pain pain control used the Melzack-Wall Gate Control perception, reduce the pain response, relieve muscle Theory in which modulation of pain occurred spasm, and reduce inflammation. The acupunc- through normal antinociceptive neuronal circuits in ture technique used affects the degree of pain con- the spinal cord.6 Based on this theory, it was pro- trol. In studies comparing EA with dry-needle posed that EA stimulates A␤ and A␦ nerve fibers acupuncture, EA produced greater brain changes on (Table 1), which would transmit impulses to the fMRI than dry needles and also elicited a better spinal cord faster than C nerve fibers and engage 15,16 analgesic effect. In other studies, bilateral EA synaptic sites on dorsal horn neurons. The later stimulation was superior to unilateral stimulation arriving pain signals from C fibers would have fewer for analgesia, and unilateral stimulation had the sites on which to synapse, because the gates would most powerful analgesic effects on the contralateral be closed (synaptic sites are already occupied) (Fig. side.17,18 EA is recommended over non-manipu- 2). Using this theory, EA was thought to induce a lated, dry-needle acupuncture for pain management segmental spinal inhibition of nociceptive inputs and is used in most studies of acupuncture analge- and result in an immediate, short-term, non–opioid- sia.13,19 fMRI data suggest that acupuncture nee- mediated analgesia because of reduced release of dle stimulation at two different depths of needling, Substance P from C fibers.6,9,23 superficial and deep, does not elicit significantly The analgesic effects of EA are more complex than different blood oxygen level-dependent (BOLD) can be described using the Gate Control theory responses.20 alone, because branches of A␦ and C fibers also

128 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) synapse with inhibitory internuncial neurons in the pain through the ␮-opioid receptor.18 EA of 10 Hz spinal cord grey matter, resulting in the release of at ST-36 significantly improved the weight-bearing inhibitory neurotransmitters that block incoming force, and this positive effect was abolished when a and outgoing pain impulses.13,19,23 EA of the A␦ selective antagonist of the ␮-opioid receptor was fibers results in the stimulation of inhibitory en- administered. kephalinergic internuncial neurons in the outer part Central sensitization (secondary hyperalgesia) of Lamina II of the spinal cord that block C fiber can be associated with tissue inflammation or pe- pain impulses. Low-frequency EA at ST-36 signif- ripheral nerve injury and is an important cause of icantly inhibited cold allodynia in a rat tail model of persistent pain. Animal models of capsaicin-in- neuropathic pain through stimulation of GABA in- duced pain have well-defined peripheral and central hibitory systems in the spinal cord, sensitization components, and therefore, they are whereas sham EA at a non-acupoint and dry-needle useful for studying the peripheral and central anal- acupuncture at ST-36 were ineffective.16 The anal- gesic effects of acupuncture. In a recent study of gesic effects of EA have also been shown to be re- the analgesic effects of EA on capsaicin-induced cen- lated to inhibition of the release of excitatory tral sensitization, EA produced a stimulation point- neurotransmitters (glutamate and aspartic acid), specific analgesic effect that was mediated by which normally transmit pain signals from the spi- activating endogenous ␮- and ␦-opioid receptors in nal cord to higher brain levels.24 the spinal cord.29 In a mouse cancer pain model, Activation of the NMDA subtype of glutamate re- EA decreased the overexpression of Substance P in ceptors and subsequent nitric oxide (NO) production the dorsal horn, increased ␤-endorphin, and reduced are important factors in central sensitization and the pain response to mechanical stimulation, show- the development of hyperalgesia.4,6,25,26 In a study ing the effectiveness of EA to control pain, even in of the role of NO in a carrageen-induced inflamma- the presence of central sensitization.30 tion model, it was suggested that EA was a biochem- High-frequency EA (100–200 Hz) not only induces ical modulator in the spinal cord and prevented the dynorphin release in the spinal cord but also in- activation of the NMDA receptors and central sen- creases the release of serotonin, epinephrine, and sitization.25 The combination of EA with ket- norepinephrine (inhibitory neurotransmitters), amine, an NMDA receptor antagonist, also which inhibit pain signals.6,13,19,31 In another rat enhanced the antihyperalgesic effect. In another neuropathic pain model, studying pain modulation rat neuropathic pain model study, EA stimulation in the PAG region, EA completely abolished hista- decreased NO synthase expression in the L4–5 spi- mine and dopamine release, which is normally in- nal cord and decreased mechanical allodynia second- creased after a painful stimulus, and increased the ary to nerve injury.26 release of norepinephrine in the PAG regions.32 Other studies have shown the profound effect of EA is thought to also enhance the effects of descend- EA on the hypothalamic-pituitary axis.6,13,19,27 ing serotoninergic pain inhibition.13 EA has been The hypothalamic-pituitary axis not only produces shown to activate neurons containing serotonin, epi- the well-known neuroendocrine effects, but it is part nephrine, and norepinephrine in the nucleus raphe of the central descending pain-inhibitory pathways magnus and locus coeruleus of the medulla oblon- involving endogenous opioids and most likely also gata, which suppress pain and hyperalgesia through plays a role in cholinergic anti-inflammatory mech- descending pathways to the spinal cord.33 anisms through the vagus nerve.28 EA has been In a study of neuropathic pain in rats, changes of shown to increase circulating ␤-endorphin in the spinal synaptic plasticity were affected by EA.34 blood, which is most likely associated with ascend- EA at a low frequency of 2 Hz at acupoints ST-36 ing afferent stimulation of the hypothalamus and and SP-6 reduced neuropathic pain and induced release of these substances from the long-term depression of the C fiber-evoked poten- pituitary.6,13,19,23,27 tials in a spinal nerve ligation model in rats. EA also activates neurons in the midbrain PAG Muscle contracture (non-voluntary muscle con- region that stimulate the descending endogenous traction) creates an energy crisis and pain in short- opioid inhibitory pathways to reduce pain (Fig. ened muscles but can be relaxed by inserting 2).4,6,13,18,23 Low-frequency EA (10–20 Hz) stimu- needles into the corresponding acupoints to restore lates the release of ␤-endorphin, enkephalin, and normal muscle physiology.4,11,35 Acupuncture can endomorphin, which activates the ␮- and ␦-opioid alleviate the pain, and it can allow the muscles to receptors, and higher-frequency (100–200 Hz) EA relax and the associated structures to return to nor- stimulates dynorphin, which activates the ␬-opioid mal patterns of motion. Intramuscular stimulation receptors to produce analgesia.13 A mixture of fre- (IMS) is a modified version of acupuncture and is quencies (low-frequency stimulation for a period fol- based on neuroanatomic principles.11 A basic tenet lowed by high-frequency stimulation) is suggested to of IMS is that acupuncture points are usually situ- be most effective, because it stimulates all opioid ated close to motor points within muscles or at mus- receptors.23 In a carrageenan-induced arthritis culotendinous junctions. Points that are effective pain model in rats, low-frequency EA pre-treatment for treatment are at the same segmental level as the had an antinociceptive effect against inflammatory presenting clinical signs or the injury. These

AAEP PROCEEDINGS ր Vol. 57 ր 2011 129 IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) points usually coincide with palpable muscle bands and that NK-1/Substance P receptors play impor- that are tender to manual pressure. Tender points tant roles in nociception and hyperalgesia at the are distributed in a segmental fashion in muscles spinal cord level.39 Electroacupuncture can effec- supplied by both dorsal and ventral nerve roots, tively decrease the pro-inflammatory cytokine of in- indicating radiculopathy. Muscles with tender terleukin-1 (IL-1) and IL-6, increase the inhibition points are shortened from spasm and contracture. cytokine of IL-4 and IL-10, and improve the internal Symptoms and signs typically disappear when the environment of occurrence and progression of rheu- tender and tight muscle bands are stimulated with matoid arthritis.40 acupuncture.11 Surface electromyography (EMG) Chronic pain syndromes often involve the auto- can measure gross muscle fiber strength and show nomic nervous system, and persistent increased the fatigue and asymmetrical recruitment associ- sympathetic tone causes regionalized hypothermia ated with myofascial pain syndromes. The typical from vasoconstriction.41 Because these pain syn- myofascial pain patient has surface EMG evidence dromes are not related to inflammation, they are of one or more inhibited muscles. Evidence of fa- unresponsive to anti-inflammatory medication. tigue shown by asymmetrical scalene muscle con- The types of pain experienced include hyperesthe- tractions and the increased activity of the muscles sia, burning, aching, throbbing, and allodynia. recorded on the EMG when an acupuncture needle Thermal imaging provides objective, measurable ev- is inserted can be shown.11 Another clinical exam- idence of the ability of acupuncture to restore nor- ple of the use of IMS is acupuncture of Ashi points mal blood flow through effects on autonomic for the treatment of piriformis muscle pain (pirifor- regulation of vasomotor tone.41 Increased sciatic mis syndrome). In a recent study of 80 cases of nerve blood flow measured in rats by laser Doppler piriformis syndrome, one-half of the cases were ran- flowmetry was observed with nerve root stimulation domly assigned to a group that received an inhibi- (100%) compared with lumbar muscle acupuncture tory-needling acupuncture method on Ashi points, (56.9%), suggesting that, in addition to its influence and the other one-half of the cases received a rou- on the pain inhibitory system, acupuncture triggers tine-needling acupuncture method at GB-30, BL-54, a transient change in blood circulation.42 and GB-34. Both groups responded positively (92% EA may also affect the motivational, behavioral, in Ashi points inhibitory-needling group and 82.5% and emotional responses to pain through effects on in transpositional acupoint routine-needling group), the hypothalamic, limbic, and higher cortical re- but stimulating Ashi points produced a significantly gions.6,19 The effects of acupuncture to calm Shen better response than routine stimulation of transpo- and reduce anxiety are well-known, and anxiety and sitional acupoints (p Ͻ 0.05).36 depression are factors in chronic pain. In a study of The midbrain PAG region not only inhibits pain changes in cortical metabolites using fMRI in de- through the release of endogenous opioids but also pressed and normal human patients, EA was shown causes changes in the heart and respiration rates to have a significant effect on brain neurochemistry and blood pressure associated with pain through the compared with controls and EA positively affected hypothalamus and autonomic nervous system. depressed patients.44 EA alters the effects of pain on viscera and blood Known variations in the response of individuals to vessels by its effects on the PAG and hypothalamic acupuncture treatment complicates the evaluation regions and descending pathways from these re- of acupuncture for pain control.9 According to the gions to the vagus nerves and parasympathetic and work by Cho et al.,9 about 28% of humans are excel- sympathetic spinal cord lower motor neurons. EA lent responders, 64% are good and average respond- also induces local spinal cord segmental reflexes ers, and 8% are weak or non-responders.9 In a pilot that affect vascular tone and other autonomic func- study of psychophysical pain responses in humans tions.6,13 EA affects the inflammatory reflex after dry-needle, EA, and sham treatments, all sub- through the autonomic nervous system, regulates jects receiving one of the acupuncture techniques the immune system, and reduces inflammation-in- had improved pain tolerance, but some responded duced hyperalgesia.13 At 10 Hz, EA significantly better to EA, and others responded better to dry reduced complete Freund’s adjuvant-induced hind needles.44 The results of this study indicate the paw edema and increased plasma levels of cortico- existence of both individual subject and acupuncture sterone, but it produced no noticeable signs of stress. mode variability in the analgesic effects of acupunc- At 10 Hz but not 100 Hz, EA suppresses inflamma- ture. This finding suggests that switching the acu- tion by activating the hypothalamus-pituitary-adre- puncture mode may be a treatment option for nal axis (HPA) and the nervous system.37 Besides unresponsive patients. the mediation by different central structures, acu- puncture may have direct effects on regulating pe- 4. Clinical Research on Acupuncture for Pain Control ripherally the release of some inflammatory and in Humans pain mediators.38 It has been shown that EA sig- A review of all the clinical research for pain control nificantly suppresses behavioral hyperalgesia in a in humans is beyond the scope of this paper, but a rat model of persistent inflammatory pain by sup- few current studies that are applicable to veterinary pressing the spinal neurokinin-1 (NK-1) receptors medicine will be discussed here. Although clini-

130 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) cians have continued their respect and reverence for creased after 15 and 30 min moxibustion (both p Ͻ tradition in their training, they have also recognized 0.05), there were no obvious changes of the VAS the need for evidence-based medicine in their prac- scores in the placebo-treated and control groups, and tice of acupuncture. The evidence base for acu- the scores of VAS in the observation group decreased puncture treatment in humans has changed. For much more obviously than the scores in the other example, in 2000, an article in Cochrane Database two groups (all p Ͻ 0.05). (2) The midwife rated the System Review45 stated that the evidence summa- uterine contraction pain: after 30 min moxibus- rized in the systematic review did not indicate that tion, the effective rate of labor analgesia was 69.5% acupuncture was effective for the treatment of back (41/59) in the observation group, which was higher pain.45 In 2005, an updated systematic review of than the rates of 45.6% (26/57) in the placebo- chronic low back pain research, within the frame- treated group and 43.1% (25/58) in the control work of the Cochrane Database System Review col- group, with significant differences between them laboration, indicated that acupuncture was more (both p Ͻ 0.05). (3) The post-partum hemorrhage effective for pain relief and functional improvement amount of the observation group was obviously than no treatment or sham treatment.46 Immedi- lower than the amounts of the placebo-treated and ate and sustained pain relief was observed in people control groups (both p Ͻ 0.05). (4) The Apgar score with low back pain from lumbar spinal canal steno- of newborn was higher in the observation and pla- sis and herniated intervertebral discs who received cebo-treated groups than the control group (both p Ͻ EA at the nerve root compared with manual acu- 0.05). puncture.42 Acupoint electrical stimulation at the Cancer pain can destroy the quality of life of hu- true acupoints, compared with placebo and sham mans and animals. Treatment with opioid analge- groups, effectively reduced postoperative pain and sics has significant adverse effects, including analgesic usage in patients with spinal surgery re- inhibition of respiratory function, constipation, ad- ceiving patient-controlled analgesia.47 diction, and tolerance that further decrease quality A randomized, controlled trial was conducted in of life. EA may be used to reduce cancer pain. 255 human practices in Germany to assess quality of In a study of neuropathic cancer pain, sarcoma cells life, costs, and cost-effectiveness of acupuncture were inoculated around the sciatic nerves of mice.30 treatment plus routine care versus routine care The presence of embedded cancer cells that induced alone in osteoarthritis patients.48 Four hundred mechanical allodynia was confirmed by MRI. EA eighty-nine patients with chronic pain caused by treatment significantly prolonged paw withdrawal osteoarthritis of the knee or hip were evaluated for latency as well as shortened cumulative lifting du- quality of life and costs at baseline and after 3 mo ration compared with tumor control, suggesting re- using health insurance funds data and standardized duced pain after EA. questionnaires. Patients receiving acupuncture In a review of five studies of 1,334 patients with had an improved quality of life but had significantly chronic knee pain, acupuncture was found to be higher costs over the 3-mo treatment period com- superior to sham acupuncture for pain reduction pared with routine care alone. This increase in and improved function.50 The differences were still costs was primarily because of the cost of acupunc- significant when patients were followed long term. ture. The study concluded, however, that acupunc- Their conclusions were that adequate acupuncture ture was an effective treatment strategy in patients treatment is superior to sham acupuncture and no with chronic osteoarthritis pain but might cost more treatment for improving pain and function in pa- than some conventional drugs.48 tients with chronic knee pain. Moxibustion at San-yin-jiao (SP 6) can relieve A systematic review and meta-analysis of ran- uterine contraction pain and has no side effect to domized controlled trials of acupuncture for neck mother and infant; it is safe, effective, and a simple pain found that acupuncture was more effective non-drug analgesia method.49 One hundred seven- than controls in the treatment of neck pain.51 A ty-four cases of singleton pregnancy and cephalic randomized controlled multicenter trial in Germany presentation primipara were single-blinded and was performed in 14,161 patients with chronic neck randomly divided into three groups: observation pain (duration Ͼ 6 mo).52 Treatment with acu- group (59 cases), placebo-treated group (57 cases), puncture added to routine care in patients with and control group (58 cases). The observation chronic neck pain was associated with improve- group was treated with moxibustion at San-yin-jiao ments in pain and reduced disability compared with (SP 6) for 30 min when the uterus cervix opening treatment with routine care alone. was 3 cm, the placebo-treated group was treated Pain is a prevalent consequence of spinal cord with moxibustion at no acupoint for 30 min, and the injury that can persist for years after the injury control group was treated with routine labor nurs- and can have a significant impact on physical and ing; the uterine contraction pain and safety of the emotional function and quality of life. In a re- mother and infant were compared among the three view of several studies, acupuncture was as effec- groups. (1) The uterine contraction pain was tested tive to treat neuropathic pain from spinal cord by the Visual Analogue Scale (VAS): the scores of injury as anticonvulsant agents and tricyclic VAS in the observation group were obviously de- antidepressants.53

AAEP PROCEEDINGS ր Vol. 57 ր 2011 131 IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) The etiology of peripheral neuropathy (PN) often cross-referencing concluded that there were 216 re- remains elusive, resulting in a lack of objective ther- ported instances of serious complications worldwide apeutic strategies. Data suggest that there is a over a 20-yr period.61 positive effect of acupuncture on PN of undefined In a report of the adverse effects of 32,000 acu- etiology, which was measured by objective parame- puncture treatments, minor adverse events, defined ters.54 In a pilot study to evaluate the therapeutic as “any ill effect, no matter how small, that is unin- effect of acupuncture on PN as measured by changes tended and non-therapeutic, even if not unex- in nerve conduction and assessment of subjective pected,” resulted from 6.71% of treatments. Most symptoms, 192 consecutive patients with PN as di- common minor events were needle site bleeding agnosed by nerve conduction studies (NCS) were (3.1%), needle site pain (1.1%), and aggravation of evaluated over a period of 1 yr. Of the 47 patients symptoms (0.96%), but 70% of symptoms subse- who met the criteria for PN of undefined etiology, 21 quently improved.62 In a second report, 574 acu- patients received acupuncture therapy according to puncturists reported adverse effects of 34,000 classical Chinese medicine, whereas 26 patients re- acupuncture treatments.63 Minor adverse events ceived the best medical care but no specific treat- occurred in 15% of cases; the most common events ment for PN. Sixteen patients (76%) in the were aggravation of symptoms (2.8%), bruising acupuncture group improved symptomatically and (1.7%), needle pain (1.2%), and needle site bleeding objectively as measured by NCS, whereas only four (0.4%). Most (86%) aggravated symptoms im- patients in the control group (15%) did. Three pa- proved, possibly indicating a healing crisis, which is tients in the acupuncture group (14%) showed no a therapeutic process involving temporary exacerba- change, and two patients showed aggravation (10%), tion of existing symptoms that precedes improve- whereas in the control group, seven patients showed ment. These two studies reported no life- no change (27%); additionally, in the control group, threatening events associated with acupuncture. 15 patients showed aggravation (58%). Impor- The extent of actual risk of acupuncture treatment tantly, subjective improvement was fully correlated is difficult to quantify; however, there is a low but with improvement in NCS in both groups. significant incidence of adverse effects, usually mi- Acupuncture combined with rehabilitation ther- nor, which includes needle pain, bruising, nausea or apy may improve motion recovery of impaired joints. syncope (mild and transient), and aggravation of Compared with rehabilitation therapy alone, EA symptoms.64 A few case reports describe serious combined with rehabilitation therapy can achieve a side effects such as pneumothorax, spinal cord in- significant effect on the motion function recovery of 55 jury, hepatitis, cellulitis, and trauma from broken or the elbow joint after fracture repair. EA and ex- embedded needles. The serious adverse affects of Ͻ ercise have a greater therapeutic effect (p 0.001) acupuncture treatment reported in the literature compared with exercise on movement disorders of may easily be prevented by straightforward precau- shoulder joint after surgical repair of fracture of the 60 56 tions. Conditions that increase the risk of com- neck of the humerus. Acupuncture combined plications in acupuncture treatment in humans with rehabilitation was superior to rehabilitation include hemophilia, advanced liver disease, antico- alone in pain score, passive range of motion of shoul- agulation therapy, diabetes, human immunodefi- der joint, muscle strength of the middle group of 57 ciency virus (HIV) infection, and other forms of the deltoid, and upper limb motion post-stroke. immunosuppression, such as high-dose corticoste- Treatment of acute soft-tissue injury of the shoulder roid administration.65 joint with EA and exercise was more effective than oral administration of ibuprofen slow-release cap- 5. Clinical Research on Acupuncture for Pain Control sules.58 Specific, one-time acupoint stimulation in Animals significantly improved gait performance statistically during geriatric ward rehabilitation.59 In a multi- Currently, much of the practice of acupuncture in ple-blinded, randomized, controlled intervention animals is based on the results of pilot research trial, gait performance was objectively measured by studies, case reports, and clinical experi- an electronic walkway before and after needling. ences. Compared with human acupuncture, the All gait parameters showed statistically significant clinical application of veterinary acupuncture is in improvement in velocity, cadence, stride length, cy- the early stages of development as a science. On cle time, step time, single support, and double sup- the basis of the findings of a systematic review per- port after verum acupuncture compared with control formed in 2006, there is no compelling evidence to treatment. recommend or reject acupuncture for any condition Acupuncture may be much safer than conven- in domestic animals. Some encouraging data do tional treatments. Previous surveys indicated that exist that warrant additional investigation in inde- there was a significant but low risk of serious side pendent rigorous trials.66 There is a mixture of effects with acupuncture in humans ranging from results in clinical trials of acupuncture for pain con- 1:10,000 to 1:100,000.60 A comprehensive review of trol in animals, but there are only a few high-quality the complementary and alternative therapies data- research studies in animals that evaluate EA for base, Medline database (1966–1993), with extensive pain control.

132 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) Analgesic effects from acupuncture have been ob- sponse on palpation). Needle EMG activity and served in horses and other species.31,67–74 Acu- twitch responses were recorded at 25 positions at puncture has been used clinically to treat lameness the trigger point and at a nearby control point dur- and chronic back pain, including fibromyalgia syn- ing the course of each horse’s acupuncture treat- drome.23,75–84 There are several studies that mea- ment. All subjects showed objective signs of sured the release of ␤-endorphin and cortisol during spontaneous electrical activity, spike activity, and equine acupuncture.23,85,86 In one study, dry-nee- local twitch responses at the myofascial trigger dle acupuncture and EA provided cutaneous analge- point sites within taut bands. The frequency of sia in horses without adverse cardiovascular and these signs was significantly greater at myofascial respiratory effects, and EA was more effective than trigger points than control sites (p Ͻ 0.05). dry-needle acupuncture for activating spinal cord EA can reduce visceral pain, regulate gastrointes- release of ␤-endorphin into the CSF of horses.86 tinal motility, and improve regional blood flow in Controlled clinical trials have shown significant animal models.23,88,89 However, EA was not as ef- improvement of thoracolumbar pain in horses using fective as butorphanol in one rectal distention objective methods of pain evaluation.83,84 In a model, and bilateral EA at Guan-yuan-shu was in- study of 15 horses with thoracolumbar pain, EA was effective in reducing the acute signs of discomfort compared with phenylbutazone and saline using induced by small intestinal distention in a clinical thoracolumbar pain scores before and after treat- model.90,91 These results indicate the need for ad- ment. Thoracolumbar pain scores were based on ditional research in acupuncture for domestic ani- behaviors recorded on videotape and were evaluated mal visceral pain. EA at Nei-guan (PC-6) and scored by a blinded, independent investigator. significantly inhibits the frequency of transient EA significantly lowered pain scores of horses with lower esophageal sphincter relaxations (TLESR) chronic thoracolumbar pain compared with phenyl- and the rate of common cavity during TLESR in butazone or saline.83 In a randomized, double- cats. This effect seems to act on the brain stem and blind, controlled trial of 23 sport horses with back may be mediated through NO, CCK-A receptor, and pain, objective measurements of pain threshold lev- ␮-opioid receptors.92 Electroacupuncture with a els were obtained with a pressure algometer.84 high frequency at ST-36 enhances lower esophageal Painful points (trigger points) were identified on sphincter pressure (LESP) as well as esophageal each horse, and baseline pain threshold measure- motility, whereas EA with a low frequency decreases ments were taken. EA was performed at GV-20 LESP. The effect of EA is acupoint-specific, and and GV-6 and bilaterally at BL-26, BL-54, BL-21, this effect seems to be mediated through gastrin, and BL-17 at a frequency of 20 Hz for 15 min and motilin, and vasoactive intestinal peptide.93 80–120 Hz for 15 min. After five treatments, pres- Cardiac MRI (CMRI), an important tool in moni- sure-induced pain was significantly reduced at trig- toring cardiovascular diseases, provides a reliable ger points in the treatment group compared with the method to monitor the effects of electroacupuncture control group. on the cardiovascular system. Ketamine/xylazine In another blinded, controlled study using an ex- cocktail anesthesia caused a transient hypertension perimental model of lameness in the horse, the ef- in the cats; EA inhibited this anesthetic-induced fects of EA were studied for pain control of the hoof hypertension and shortened the post-anesthesia re- sole.23 Lameness scores were assigned based on an covery time, countering the negative effects of anes- established lameness scale with two independent thetics on cardiac physiology.94 evaluators; one evaluator assessed lameness by In a recent study of the use of EA for postoperative watching video only and was blinded to treatment. pain in intervertebral disk disease in dogs, the total Lameness was evaluated before tightening the dose of fentanyl administered during the first 12 h screw, after tightening the screw, after treatment after surgery was significantly lower in the EA with either EA, a 0.5% bupivacaine nerve block (pos- group than in the control group, but dosages of an- itive control), or a saline nerve block (negative con- algesics administered from 12 to 72 h after surgery trol), immediately after loosening the screw, and 95 did not differ between groups. Pain scores were min later. The EA caused a significant reduction in significantly lower in the treatment group than in the lameness score compared with the saline nerve the control group 36 h after surgery but did not block (negative control) as well as a significant in- differ significantly between groups at any other crease in plasma ␤-endorphin. time.95 The clinical efficacy of EA and acupuncture Equine myofascial trigger points can be identified combined with medication for the treatment of tho- and have similar objective signs and electrophysio- racolumbar intervertebral disc herniation in dogs logical properties as those signs documented in hu- was compared with dogs treated with conventional man and rabbit skeletal muscle tissue.87 Four medicines alone in paraplegic dogs with intact deep horses with chronic pain signs and impaired perfor- pain perception.96 Treatment efficacy was evalu- mance showed signs compatible with the diagnosis ated by postoperative neurologic function, ambula- of myofascial trigger points in their brachiocephalic tion, relapse, complication, and urinary function. muscle (i.e., localized tender spots in a taut band of The results suggest that a combination of electro-AP skeletal muscle that produced a local twitch re- and AP with conventional medicine is more effective

AAEP PROCEEDINGS ր Vol. 57 ր 2011 133 IN-DEPTH: INTEGRATIVE MEDICINE (COMPLEMENTARY & ALTERNATIVE MEDICINE) than conventional medicine alone in recovering am- Other than pain relief, acupuncture does not di- bulation, relieving back pain, and decreasing re- rectly address any specific clinical sign but normal- lapse. EA was more effective than decompressive izes physiological homeostasis and promotes self- surgery for recovery of ambulation and improve- healing through normal endogenous pathways. ment in neurologic deficits in dogs with long-stand- Thus, acupuncture, in terms of its therapeutic mech- ing severe deficits attributable to thoracolumbar anisms, is non-specific.9 As a physiological ther- IVDD.97 The clinical success for dogs that under- apy, the efficacy of acupuncture depends on the went decompressive surgery and EA was pathology involved and the healing potential intrin- intermediate. sic to each patient. Therefore, acupuncture effec- In controlled, double-blind clinical trial of chronic tiveness varies from person to person and animal to hip pain from hip dysplasia in 78 dogs, the effect of animal. gold bead implants in acupoints was compared with In conclusion, there is a well-researched scientific a sham treatment 2 wk, 3 mo, and 6 mo after treat- basis for the mechanisms of acupuncture analgesia, 98 ment. The dogs with gold bead implants in acu- the extent and depth of which continues to expand. points had reduced pain and greater mobility As well, there are growing numbers of human trials compared with control dogs receiving the sham supporting the use of acupuncture as an evidence- treatment. based practice for pain management in human med- EA may be combined with conventional anesthetic icine. Although the number of well-designed agents to reduce dose requirements for maintenance clinical studies in veterinary medicine is lagging of anesthesia and improve cardiopulmonary func- 90,99 behind human medicine, the basic science research tion. In a study of goats, EA plus low-dose xy- has been done in species with neurophysiology more lazine provided analgesia that was significantly 99 similar to non-primate animals than humans, and better than EA or xylazine alone. Furthermore, therefore, the scientific basis for the use of acupunc- EA plus xylazine administration at 0.1 mg/kg pro- ture in domestic animals is clear. Although there vided better analgesia than xylazine alone at 0.4 is research to support EA as an evidence-based mg/kg. practice for the management of back pain in horses, As is the case for humans, few adverse side effects additional studies are needed in other clinical situ- have been associated with acupuncture in animals. ations where analgesia is required. As contempo- In a review of 1,292 acupuncture treatments that rary conventional biomedical and laboratory were performed on 221 animals (cats, cattle, dogs, research merges with the practical clinical experi- and horses), adverse reactions to acupuncture nee- ence of traditional Chinese medicine, it is reasonable dles totaled 4 of 12,274 needles or approximately 1 to believe that the neurophysiologic mechanisms of per 3,000 needles.100 Two of these reactions con- actions of acupuncture will be further understood, sisted of transient superficial edema of the skin, and and it will be shown to be an effective means of because they did not require treatment, did not ap- managing many different types of acute and chronic pear painful, and did not show other more serious pain as well as other disorders. signs, they were considered to be clinically trivial. There was one abscess, which resolved with antibi- otic treatment, and one seizure event in a 7-yr-old References spayed female Beagle that resolved without treat- 1. World Health Organization (WHO). Acupuncture: review ment and did not reoccur within a 7-mo follow-up and analysis of reports on controlled clinical trials (2003). period. Neither complication required hospitaliza- Available online at http://apps.who.int/medicinedocs/en/d/ tion nor was life-threatening. There were 377 Js4926e/4.1.html. Accessed on. 2. Kelly RB. Acupuncture for pain. Am Fam Physician treatments of 74 horses using a total of 2,865 nee- 2009;80:481–484. dles. A 10-yr-old Hanoverian gelding being treated 3. Horton A, Macpherson H. Acupuncture for chronic pain: for back pain and palmar heel pain of the left fore- is acupuncture more than an effective placebo? A system- limb experienced a mild local swelling on the axial atic review of pooled data from meta-analyses. Pain Pract surfaces of heel bulbs on the treated foot for 1 wk 2010, Mar-Apr; 10(2):94–102. 4. Baldry PE. Acupuncture, trigger points, and musculoskel- after its treatment. Treatment was resumed, and etal pain: a scientific approach to acupuncture for use by 13-mm needles were placed in the extranavicular doctors and physiotherapists in the diagnosis and manage- points; no additional adverse events were noted. ment of myofascial trigger point pain, 3rd ed. Brookline, Although safe in most conditions, acupuncture MA: Elsevier, Churchill Livingstone, 2005;45–56. should be used with caution in animals with debili- 5. Travel JG, Simons DG. Myofascial pain and dysfunction: the trigger point manual. Baltimore, MD: Williams & tation, frailty, or febrile illness. Needles should not Wilkins, 1983:29. be inserted directly into skin infections, ulcers, tu- 6. Steiss J. Neurophysiological basis of acupuncture. In: mors, or scar tissue. There is a traditional contra- Schoen AM, ed. 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