1. Goals of treatment in managing visceral pain
In this first section of the presentation on the management of visceral pain, we will review the goals of managing visceral pain.

2. Goals in the Management of Visceral Pain
Address underlying pathology
Alleviate symptoms
The goals in the management of visceral pain are to address the underlying pathology and to alleviate the symptoms. The treatment for visceral pain should not be delayed unless it would obscure the diagnostic workup.
Treatment should not be delayed unless it would obscure the diagnostic workup
Giamberardino MA. Pain Clinical Updates. 2005;XIII(6):1-6; IASP. Available at: Accessed 1 December, 2014.

3. Goals in the Management of Visceral Pain
Address underlying pathology
 Parallel treatment 
Alleviate symptoms
In theory, can defer pain management until symptom cause identified
Masking pain may confound diagnostic process and delay recognition of a potentially life-threatening condition
In practice, a clear cause of each symptom may never be proven
Symptomatic treatment should not be withheld when a treatable condition has been identified
In managing patients with visceral pain, addressing the underlying pathology and alleviating the symptoms should progress in parallel. In theory, one can defer pain management until symptom cause identified, since masking pain may confound diagnostic process and delay recognition of a potentially life-threatening condition. In practice however, a clear cause of each symptom may never be proven. Therefore, prolonged fruitless investigations should end before new, procedure-related pain has been introduced or psychological problems become insurmountable. It is important to remember that there is no reason to withhold symptomatic treatment once a treatable condition has been identified.
Prolonged/repetitive visceral afferent barrage into CNS increases risk of long-term sensitization and consequences (e.g., referred hyperalgesia, trophic changes)
Giamberardino MA. Pain Clinical Updates. 2005;XIII(6):1-6.

4. Overview of the Treatment of Visceral Pain
Symptomatic treatment relies mainly on pharmacotherapy
Analgesics
Acetaminophen
NSAIDs/coxib
Opioids
Non-analgesic agents
Antidepressants
α2δ ligands
Nitrates for angina
Histamine receptor agonists or PPIs for ulcer/gastritis
Deep infiltration of muscle layer of referred area with local anesthetic may be helpful
Non-pharmacological treatments are also important
Cognitive behavioral therapy
Meditation
Psychotherapy
The symptomatic treatment relies mainly on pharmacotherapy. Drug classes used for this purpose include analgesics like acetaminophen, NSAIDs or coxibs, and Opioids, as well as non-analgesic agents like antidepressants, α2δ ligands, nitrates for angina, histamine receptor agonists or PPIs for ulcer or gastritis, and deep infiltration of muscle layer of referred area with local anesthetic may be helpful. Non-pharmacological treatments are also important for the management of visceral pain. These include cognitive behavioral therapy, meditation, and psychotherapy.
PPI = proton pump inhibitor
Giamberardino MA. Pain Clinical Updates. 2005;XIII(6):1-6.

5. Non-pharmacological Management of Visceral Pain
This section will give an overview of the non- pharmacological management of visceral pain.

6. Benefits of Non-pharmacological Methods in Treating Visceral Pain
Increase individual’s feeling of control
Decrease the feeling of weakness
Improve activity level and functional capacity
Reduce stress and anxiety
Reduce pain behavior and focused pain level
Reduce needed dosage of analgesic drugs  decrease drug adverse effects
The benefits of non-pharmacological management of visceral pain include an increase individual’s feeling of control, a decrease the feeling of weakness, improvement of activity level and functional capacity, reduced stress and anxiety, reduced pain behavior and focused pain level, and finally a reduction of the needed dosage of analgesic drugs which will lead to a decrease of adverse drug effects.
Demir Y Available at: Accessed 8 January 2015.

7. Multimodal Treatment of Pain Based on Biopsychosocial Approach
Lifestyle management
Sleep hygiene
Stress management
Interventional pain
management
Physical therapy
Pharmacotherapy
Speaker’s Notes
The 2011 Institute of Medicine (IOM) pain report suggested that a mind-body approach should be used when caring for patients with pain.
The biopsychosocial approach, combining physical and emotional factors in assessing and treating chronic pain, offers a uniquely valuable clinical perspective. This mind-body perspective is now generally accepted by pain researchers and has been found useful by clinicians in various disciplines.
This animated slide lists components that might be included in such a multimodal approach to pain therapy.
References
Gatchel RJ et al. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull 2007; 133(4):
Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.; National Academies Press; Washington, DC: 2011.
Mayo Foundation for Medical Education and Research. Comprehensive Pain Rehabilitation Center Program Guide. Mayo Clinic; Rochester, MN: 2006.
Occupational therapy
Education
Complementary therapies
Biofeedback
Gatchel RJ et al. Psychol Bull 2007; 133(4): ; Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.; National Academies Press; Washington, DC: 2011; Mayo Foundation for Medical Education and Research. Comprehensive Pain Rehabilitation Center Program Guide. Mayo Clinic; Rochester, MN: 2006.

8. Various Non-pharmacological Treatments Are Available for Visceral Pain
Physiotherapy
Psychotherapy/CBT
Multimodal pain management
programs
No modality is universally recommended
Patient education
Alternative therapies and spiritual healing
Speaker’s Notes
Various non-pharmacological treatments are available to help manage visceral pain. These include communication strategies, such as patient education; physical modalities, such as physiotherapy; psychological modalities, such as cognitive behavioral therapy; and a wide variety of alternative spiritual and religious-based treatments, such as meditation.
In general non-pharmacological treatment is complementary to drug therapy and, given their presumed safety, non-pharmacologic treatments should be considered whenever appropriate.
CBT = cognitive behavioral therapy

9. Pharmacological Management of Visceral Pain

10. Overview of Pharmacological Management of Visceral Pain
Visceral pain is included with somatic and nociceptive pain in most clinical trials
Difficult to select appropriate drug choices for visceral pain
There may be differences in responses to analgesics
Analgesic combinations likely to be more effective than single agents
Analgesic dose-response relationships for visceral pain may be different than those for somatic pain
Speaker’s Notes
Visceral pain is included with somatic and nociceptive pain in most clinical trials
Difficult to determine appropriate drug choices for visceral pain
Differences between somatic and visceral pain neurotransmission, neurotransmitters, channels and receptors suggests there may be differences in responses to analgesics
Analgesic combinations likely to be more effective than single agents
Analgesics ineffective as single agents or at a particular dose may have additive analgesia for visceral pain when combined with a second analgesic
Analgesic dose-response relationships for visceral pain may be different than those for somatic pain
Reference
Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat. 2012;2012:
Unlikely that one analgesic or targeted agent will significantly reduce most visceral pain because multiple neurotransmitters, channels, and receptors are responsible
Davis MP. Pain Res Treat. 2012;2012:

11. Analgesics Affect Different Parts of the Pain Pathway
Descending
modulation
Dorsal
horn
Ascending
input
Spinothalamic
tract
Dorsal root
ganglion
Peripheral
nerve
nociceptors
Pain
Trauma
α2δ ligands
Antidepressants
nsNSAIDs/coxibs
Opioids
Local anesthetics
Speaker’s Notes
This slide summarizes the various analgesics that affect different parts of the pain pathway.
References
Gottschalk A et al. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001; 63(10):
Verdu B et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68(18):
Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug
Adapted from: Gottschalk A et al. Am Fam Physician 2001; 63(10): ; Verdu B et al. Drugs 2008; 68(18):

12. Overview of Pharmacological Treatments for Visceral Pain
Drug(s)
Comments
Acetaminophen
Weak COX-2 inhibitor and selective COX-3 inhibitor
Little known about efficacy in managing visceral pain
More effective in combination with NSAIDs
NSAIDs/coxibs
Block COX-1 (NSAIDs) and COX-2 (NSAIDs, coxibs)
Alleviate pain but adverse events (especially GI) preclude chronic use
More effective in combination with acetaminophen
Opioids
Modify perception, modulate transmission, and affect pain signal transduction
May cause hyperalgesia – dose reduction may improve pain control
Adverse events, risk of abuse, addiction, tolerance, and physical dependence limit use
Antidepressants
Modulate interactions between CNS and enteric nervous system;  visceral hypersensitivity
TCAs most studied – agents that modify serotonergic transmission may be useful
Help with anxiety and depression often experienced with visceral pain
α2δ Ligands
Anticonvulsants: gabapentin, pregabalin
Bind to α2δ subunit of voltage-dependent Ca2+ ion channels in CNS
May be helpful in managing visceral pain but little data supports use
All use in treating visceral pain is considered off-label
Speaker’s Notes
References
Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat ;2012:
Patrizi F, Fredman SD, Pascual-Leone A, Fregni F. Novel therapeutic approaches to the treatment of chronic abdominal visceral pain. The Scientific World J. 2006;6:
Gastrosource. Non-steroidal Anti-inflammatory Drug (NSAID)-Associated Upper Gastrointestinal Side- Effects. Available at: Accessed: December 4, 2010.
Vane JR, Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 1995; 44(1):1-10.
Clemett D, Goa KL. Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain. Drugs 2000; 59(4):
Grosser T et al. In: Brunton L et al (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. (online version). McGraw-Hill; New York, NY: 2010.
Crowell MD, Jones MP, Harris LA et al. Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes. Curr Opin Investig Drugs. 2004;5(7):
Fioramonti J, Bueno L. Centrally acting agents and visceral sensitivity. Gut. 2002; 51(Suppl 1): i91–i95.
Dalton CB, Drossman DA. The use of antidepressants in the treatment of irritable bowel syndrome and other functional GI disorders. Available at: handouts/IBS%20and%20Antidepressants.pdf. Accessed 8 January, 2015.
Attal N, Finnerup NB. Pharmacological management of neuropathic pain. Pain Clinical Updates 2010; 18(9):1-8.
Lacy BE, Weiser K, De Lee R. The treatment of irritable bowel syndrome. Therap Adv Gastroenterol ;2(4):
COX = cyclooxygenase; coxib = COX inhibitor; CNS = central nervous system; NSAID = non-steroidal anti-inflammatory drug; TCA = tricyclic antidepressant
Davis MP. Pain Res Treat. 2012;2012:265605; Patrizi F et al. The Scientific World J. 2006;6:472-90; Davis MP. Pain Res Treat. 2012;2012:265605; Gastrosource. Available at: Vane JR, Botting RM. Inflamm Res. 1995; 44(1):1-10; Clemett D, Goa KL. Drugs. 2000; 59(4):957-80; Grosser T et al. In: Brunton L et al (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. (online version). McGraw-Hill; New York, NY: 2010; Crowell MD et al. Curr Opin Investig Drugs. 2004;5(7):736-42; Fioramonti J, Bueno L. Gut. 2002; 51(Suppl 1): i91–i95; Dalton CB, Drossman DA. Available at: Attal N, Finnerup NB. Pain Clinical Updates. 2010; 18(9):1-8; Lacy BE et al. Therap Adv Gastroenterol. 2009;2(4):

13. Acetaminophen in the Management of Visceral Pain
Weak COX-2 inhibitor and selective COX-3 inhibitor
Increases brainstem serotonin neurotransmission
Redirects beta-endorphin
Inhibits 5-HT 3 receptors, which are pronociceptive
Although commonly used for pain, little is known about its efficacy in managing visceral pain
Most studies do not focus on visceral pain
May be more efficacious in combination with NSAIDs
Systematic review: NSAID + acetaminophen combinations superior to acetaminophen alone in 85% of studies and to NSAIDs alone in 64% of studies
Speaker’s Notes
Reference
Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat. 2012;2012:
Acetaminophen is more effective in managing visceral pain when used in combination with NSAIDs
5-HT = serotonin; COX = cyclooxygenase; NSAID = non-steroidal anti-inflammatory drug
Davis MP. Pain Res Treat. 2012;2012:

14. NSAIDs/coxibs in the Management of Visceral Pain
Most-used analgesic drugs1
Effective but cause several side effects that preclude chronic use1
May fail to relieve chronic pain completely1
Act by inhibiting production of prostaglandins1
In renal or biliary colic, NSAIDs may involve acetylcholine blockade2
May be more efficacious in combination with acetaminophen2
NSAID + acetaminophen combinations superior to acetaminophen alone in 85% of studies and to NSAIDs alone in 64% of studies
NSAIDs superior to anticholinergics and opioids in relieving renal colic2
Speaker’s Notes
Reference
Patrizi F, Fredman SD, Pascual-Leone A, Fregni F. Novel therapeutic approaches to the treatment of chronic abdominal visceral pain. The Scientific World J. 2006;6:
Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat. 2012;2012:
Because chronic visceral pain is not usually associated with injury and inflammation, NSAIDs/coxibs might not be suitable for this condition1
1. Patrizi F et al. The Scientific World J. 2006;6:472-90; 2. Davis MP. Pain Res Treat. 2012;2012:

15. COX-2 Is Involved in Central Sensitization
Central induction of COX-2 increases prostaglandin production
PGE2 stimulation of EP receptors in the dorsal horn will:
Activate PKC, phosphorylating and further enhancing NMDA channel opening
Directly activate certain dorsal horn neurons by opening EP2 receptor linked ion channels
Reduced inhibitory transmission of glycinergic inter-neurons
Increased depolarization and excitability of dorsal horn neurons
Speaker's Notes
Inflammation induces cyclooxygenase-2 (COX-2) activity and results in the release of prostanoids. Prostanoids in turn sensitize peripheral nociceptors and produce localized pain hypersensitivity.
Central production of interleukin-1, as a result of peripheral inflammation, promotes central COX-2 expression and accordingly increases the level of prostaglandin E2 in the cerebrospinal fluid. The elevated levels of prostanoids in the central nervous system (a) propagate and sustain peripheral hypersensitivity by continually promoting neurotransmitter release from the primary nociceptive afferents and (b) directly activate central prostanoid EP2 receptors thereby heightening the excitability of dorsal horn neurones, triggering the release of glutamate and substance P which activate NMDA and natural killer (NK) receptors respectively and causing disinhibition of the glycinergic interneurones. This is termed central sensitization and eventually produces either a state of secondary hyperalgesia or allodynia.
References
Ahmadi S et al. PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci 2002; 5(1):34-40.
Baba H et al. Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J Neurosci 2001; 21(5):
Samad TA et al. Interleukin-1beta-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001; 410(6827):471-5.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
NMDA = N-methyl-D-aspartate; PGE2 = prostaglandin E2; PKC = protein kinase C
Ahmadi S et al. Nat Neurosci 2002; 5(1):34-40; Baba H et al. J Neurosci 2001; 21(5):1750-6; Samad TA et al. Nature 2001; 410(6827):471-5; Woolf CJ, Salter MW. Science 2000; 288(5472):

16. COX-2 Inhibition Minimizes Sensitization
Signal for COX-2 induction likely to persist with peripheral inflammation
To minimize sensitization, COX-2 should be inhibited centrally and in the periphery
As early as possible
Continued until peripheral inflammation resolved
Ideal COX-2 inhibitor should be able to act in periphery as well as centrally
Should readily cross blood-brain barrier
Speaker’s Notes
Inflammation in the periphery (mediated by COX-2) results in peripheral sensitization as well as the signaling of central COX-2 induction and sensitization.
Thus, the best analgesic strategy would be to block COX-2 in both the periphery and in the central nervous system early to minimize any sensitization.
Since the signaling for COX-2 induction both centrally and in the periphery is likely to persist with the inflammation, the COX-2 blockade must continue until the peripheral inflammation is resolved.
References
Samad TA et al. Interleukin-1beta-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001; 410(6827):471-5.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
Samad TA et al. Nature 2001; 410(6827):471-5; Woolf CJ, Salter MW. Science 2000; 288(5472):

17. Opioids in the Management of Visceral Pain
May cause hyperalgesia
Increased pain intensity extent of pain area
Radiation with reduced responsiveness to opioids
Mimics pain associated with progression of underlying pathology
Physicians who are unaware of this phenomenon may increase opioid dose, only to worsen the visceral pain
Addition of adjuvant analgesics or opioid rotation useful in in managing opioid-induced hyperalgesia
NSAID, acetaminophen, and opioid combinations may be additive or synergistic
Antidepressants + opioids may reduce visceral pain due to inhibition of sodium channels, NMDA receptors, P2X channels, and prostaglandins
Speaker’s Notes
May cause hyperalgesia
Increased pain intensity extent of pain area
Radiation with reduced responsiveness to opioids
Mimics pain associated with progression of underlying pathological condition
Physicians who are unaware of this phenomenon may increase opioid dose, only to worsen the visceral pain
Addition of adjuvant analgesics or opioid rotation useful in in managing opioid- induced hyperalgesia
Alters downstream signalling, resets analgesic response
NSAID, acetaminophen, and opioid combinations may be additive or synergistic
Antidepressants + opioids may reduce visceral pain due to inhibition of sodium channels, NMDA receptors, P2X channels, and prostaglandins
Reference
Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat. 2012;2012:
Paradoxically, opioid dose reduction may improve pain control
NMDA = N-methyl-D-aspartate; NSAID = non-steroidal anti-inflammatory drug
Davis MP. Pain Res Treat. 2012;2012:

18. Opioids and Pain Management
Opioid Receptor
Response Mu
Supraspinal analgesia, respiratory depression, sedation, miosis, euphoria, cardiovascular effects, pruritis, nausea/vomiting, decreased gastrointestinal motility, dependence, tolerance
Delta
Analgesia, euphoria, dysphoria, psychotomimetic effects
Kappa
Spinal analgesia, dysphoria, psychotomimetic effects, miosis, respiratory depression, sedation
Speaker’s Notes
Opioid receptors are located in both the central nervous system (CNS) and throughout the peripheral tissues. The different types of opioid receptors (mu, kappa, and delta) are normally stimulated by endogenous peptides (endorphins, enkephalins, and dynorphins) produced in response to noxious stimulation. Exogenous opioids produce analgesic effect by mimicking the actions of endogenous opioid peptides in the central nervous system by binding to endogenous opioid receptors present centrally and peripherally.
Mu receptors are found primarily in the brainstem and medial thalamus. Mu receptors are responsible for supraspinal analgesia, respiratory depression, euphoria, sedation, decreased gastrointestinal motility, and physical dependence.
Delta receptors are located largely in the brain and their effects are not well studied. They may be responsible for analgesia, euphoria, dysphoria, psychotomimetic effects.
Kappa receptors are found in the limbic and other diencephalic areas, brain stem, and spinal cord, and are responsible for spinal analgesia, sedation, dyspnea, dependence, dysphoria, and respiratory depression.
References
Gourlay GK. Advances in opioid pharmacology. Support Care Cancer 2005; 13(3):153-9.
Reisine T et al. In: Hardman JG et al (eds). Goodman and Gilman’s: The Pharmacological Basics of Therapeutics. 9th ed. McGraw-Hill; New York, NY: 1996.
Trescot AM et al. Opioid pharmacology. Pain Physician 2008; 11(2 Suppl):S
Gourlay GK. Support Care Cancer 2005; 13(3):153-9.;Reisine T et al. In: Hardman JG et al (eds). Goodman and Gilman’s: The Pharmacological Basics of Therapeutics. 9th ed. McGraw-Hill; New York, NY: 1996.; Trescot AM et al. Pain Physician 2008; 11(2 Suppl):S Gourlay GK. Supp Care Cancer. 2005;13:153-9.

19. Opioids Modulate Control of “ON” and “OFF” Cells
Opioid stimulation of mu-receptors on “ON” cells
Reduced “ON” cell activity
Reduced facilitation of pain transmission at dorsal horn
Less pain
Opioid stimulation of mu-receptors on GABA-ergic interneurons innervating “OFF” cells
Reduced GABA-ergic interneuron activity
Reduced inhibition of “OFF” cells
Increased “OFF” cell inhibition of pain transmission at dorsal horn ON
GABA
Opioid
(-)
(-) Pain transmission (+)
Rostral ventromedial
medulla
Spinal cord
dorsal horn
OFF
m-receptor
(-)
Speaker's Notes
There are two groups of neurons within the rostral ventromedial medulla that exhibit distinct responses to opioids. 'On-cells' have -receptors and are thus directly inhibited by opioids. Stimulation of mu-receptors on ‘on cells’ leads to reduced pain transmission at the level of the dorsal horn. 'Off-cells' are activated, indirectly by opioids. Specifically, opioids bind to -receptors present on GABAergic interneurons, which then negatively regulate ‘off cells” and result in a net inhibitory effect on nociceptive processing.
Reference
Fields HL et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
GABA = γ-aminobutyric acid
Fields HL et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.

20. Opioids Can Induce Hyperalgesia
Primary hyperalgesia
Sensitization of primary neurons  decrease threshold to noxious stimuli within site of injury
May include response to innocuous stimuli
Increase pain from suprathreshold stimuli
Spontaneous pain
Secondary hyperalgesia
Sensitization of primary neurons in surrounding uninjured areas
May involve peripheral and central sensitization
Speaker's Notes
Opioid-induced hyperalgesia refers to the state of nociceptive sensitization triggered by exposure to opioids. Details on the molecular mechanism of opioid-induced hyperalgesia remain ill-defined although it is believed that the complex process involves neuroplastic changes of pronociceptive pathways within the peripheral and central nervous system.
Five mechanisms involving the following have been purported to be involved in opioid-induced hyperalgesia are the:
Central glutaminergic system – N-methyl-D-aspartate (NMDA) activation and the subsequent downstream events
Spinal dynorphins – continuous infusion of -receptor agonists promote the release of excitatory neuropeptides, e.g., calcitonin gene-related peptide from primary afferents
Descending facilitation – “on cells” and “off cells”
Genetic mechanisms – catechol-O-methyltransferase (COMT) polymorphism resulting in different levels of synaptic dopamine/noradrenaline following neurotransmitter release
Decreased reuptake and enhanced nociceptive response – enhanced responsiveness to glutamate and substance P, β2 adrenergic receptor upregulation
Primary hyperalgesia occurs when there is sensitization of primary nociceptors resulting in a heightened sensation to both noxious and innocuous stimuli.
Secondary hyperalgesia manifests “downstream” from the initiating nociceptive stimulus and peripheral injury and may be resultant of peripheral and central sensitization.
References
Dolan S, Nolan AM. N-methyl D-aspartate induced mechanical allodynia is blocked by nitric oxide synthase and cyclooxygenase-2 inhibitors. Neuroreport 1999; 10(3):
Raja SN et al. In: Wall PB, Melzack R (eds). Textbook of Pain. 4th ed. Churchhill Livingstone; London, UK: 1999.
Woolf CJ. A new strategy for the treatment of inflammatory pain. Prevention or elimination of central sensitization. Drugs 1994; 47(Suppl 5):1-9.
Dolan S, Nolan AM. Neuroreport 1999; 10(3):449-52; Raja SN et al. In: Wall PB, Melzack R (eds). Textbook of Pain. 4th ed. Churchhill Livingstone; London, UK: 1999; Woolf CJ. Drugs 1994; 47(Suppl 5):1-9.

21. Opioids Can Induce Allodynia
Pain evoked by innocuous stimuli
Central sensitization  pain produced by A fibers
Possibly mediated by spinal NMDA receptors
Speaker's Notes
Allodynia is pain that is elicited by innocuous stimuli. It is the predominant symptom of opioid-induced hyperalgesia that is brought on by very high and escalating opioid doses.
Allodynia arises from central sensitization whereby A fiber-mediated mechano-signals are transmitted at the central level as nociceptive signals. There is some evidence that the glutaminergic NMDA-receptor class is involved and mediates the neurotransmission process.
References
Dolan S, Nolan AM. N-methyl D-aspartate induced mechanical allodynia is blocked by nitric oxide synthase and cyclooxygenase-2 inhibitors. Neuroreport 1999; 10(3):
Raja SN et al. In: Wall PB, Melzack R (eds). Textbook of Pain. 4th ed. Churchhill Livingstone; London, UK: 1999.
Woolf CJ. A new strategy for the treatment of inflammatory pain. Prevention or elimination of central sensitization. Drugs 1994; 47(Suppl 5):1-9.
NMDA = N-methyl-D-aspartate
Dolan S, Nolan AM. Neuroreport 1999; 10(3):449-52; Raja SN et al. In: Wall PB, Melzack R (eds). Textbook of Pain. 4th ed. Churchhill Livingstone; London, UK: 1999; Woolf CJ. Drugs 1994; 47(Suppl 5):1-9.

22. Adverse Effects of Opioids
System
Adverse effects
Gastrointestinal
Nausea, vomiting, constipation
CNS
Cognitive impairment, sedation, lightheadedness, dizziness
Respiratory
Respiratory depression
Cardiovascular
Orthostatic hypotension, fainting
Other
Urticaria, miosis, sweating, urinary retention
Speaker’s Notes
The use of opioids in pain management can be associated with a variety of adverse effects, as shown on this slide. Gastrointestinal side effects can include nausea, vomiting and constipation, while central nervous system effects may include cognitive impairment, sedation, lightheadedness, and dizziness. Respiratory depression, orthostatic hypotension, fainting, urticaria, miosis, sweating and urinary retention are among the other potential adverse effects of opioids.
References
Moreland LW, St Clair EW. The use of analgesics in the management of pain in rheumatic diseases. Rheum Dis Clin North Am 1999; 25(1):
Yaksh TL, Wallace MS. In: Brunton L et al (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. (online version). McGraw-Hill; New York, NY: 2010.
World Health Organization. Understanding Health Professionals’ Fear of Opioids. Available at: Accessed: October 17,
Additional Opioid Use Concerns
Abuse and addictive potential
Tolerance and physical dependence
Administrative burden in distribution and monitoring due to scheduled status
CNS = central nervous system
Moreland LW, St Clair EW. Rheum Dis Clin North Am 1999; 25(1):153-91; Yaksh TL, Wallace MS. In: Brunton L et al (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. (online version). McGraw-Hill; New York, NY: 2010; World Health Organization. Understanding Health Professionals’ Fear of Opioids. Available at: Accessed: October 17, 2013.

23. Additional Opioid Concerns
Abuse and addictive potential
Tolerance and physical dependence
Administrative burden in distribution and monitoring due to scheduled status
Speaker’s Notes
Even though opioids remain the mainstay of pain therapy, various issues with opioid pharmacology and prescription have resulted its underuse. Specifically, opioids have a symphony of effects – both beneficial and detrimental depending on a variety of factors. Accordingly, opioid management of pain requires expertise and training. This slide provides three reasons why clinicians are often hesitant to provide a prescription for opioid therapy.
Reference
World Health Organization. Understanding Health Professionals’ Fear of Opioids. Available at: Accessed: October 17, 2013.
World Health Organization. Understanding Health Professionals’ Fear of Opioids. Available at: Accessed: October 17, 2013.

24. Antidepressants in the Management of Visceral Pain
Visceral pain syndromes may be effectively treated by a number of therapies that modulate interactions between the central and enteric nervous systems
Antidepressants may be efficacious for treatment of these syndromes
TCAs most studied
Other antidepressants may be useful because serotonin modifies sensation in the gut
Agents that modify serotonergic transmission may be useful in the moderation of visceral pain syndromes
Selective serotonin reuptake inhibitors may be useful
Speaker’s Notes
References
Crowell MD, Jones MP, Harris LA et al. Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes. Curr Opin Investig Drugs. 2004;5(7):
Fioramonti J, Bueno L. Centrally acting agents and visceral sensitivity. Gut. 2002; 51(Suppl 1): i91–i95.
Crowell MD et al. Curr Opin Investig Drugs. 2004;5(7):736-42; Fioramonti J, Bueno L. Gut. 2002; 51(Suppl 1): i91–i95.

25. Antidepressants in the Management of Visceral Pain
Antidepressants work at the level of brain and spinal cord to block pain messages between the gastrointestinal tract and the brain  reduces visceral hypersensitivity
May help recover the brain’s ability to respond to pain signals properly
May stimulate nerve cell growth and possibly restore more normal nerve function in the in the brain and intestines over time
Patients may require antidepressant treatment for 6 months to 1 year
Therapy may need to be extended in patients with a longer history of visceral pain
Speaker’s Notes
References
Dalton CB, Drossman DA. The use of antidepressants in the treatment of irritable bowel syndrome and other functional GI disorders. Available at: Accessed 8 January, 2015.
Using antidepressants can also help with the anxiety and depression often experienced by individuals with visceral pain
Dalton CB, Drossman DA. Available at: Accessed 8 January, 2015.

26. Antidepressants Used in the Management of Visceral Pain
Class and Drug
Adverse Effects
TCA
Amitriptyline
Imipramine
Desipramine
Nortriptyline
Dry mouth
Difficulty sleeping
Difficulty urinating
Sexual difficulties
Constipation
Dizziness
Drowsiness
SSRI
Citalopram
Escitalopram
Paroxetine
Sertraline
Fluoxetine
Nervousness
Vivid dreams
Sleep disturbances
Diarrhea
SNRI
Venlafaxine
Duloxetine
Desvenlafaxine
Milnacipram
Nausea
Headache
Changes in liver chemistry (rare)
Speaker’s Notes
References
Dalton CB, Drossman DA. The use of antidepressants in the treatment of irritable bowel syndrome and other functional GI disorders. Available at: Accessed 8 January, 2015.
SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant
Dalton CB, Drossman DA. Available at: Accessed 8 January, 2015.

27. Suggested Mechanisms of Analgesic Action of Antidepressants
Mechanism of Action
Site of Action
TCA
SNRI
Reuptake inhibition
Serotonin
Noradrenaline +
Receptor antagonism
α-adrenergic
NMDA -
(+) milncipran
Blocking or activation of ion channels
Sodium channel blocker
Calcium channel blocker
Potassium channel activator
(+) venlafaxine/ - duloxetine ?
Increasing receptor function
GABAB receptor
+ amitriptyline/ desipramine
Opioid receptor binding/ opioid-mediated effect
Mu- and delta-opioid receptor
(+)
(+) venlafaxine
Decreasing inflammation
Decrease of PGE2 production
decrease of TNFα production
Speaker's Notes
TCAs and SNRIs are antidepressants with proven analgesic effects. Notably, tricyclic antidepressants persists as one of the first-line therapies for neuropathic pain and importantly, these antidepressants elicit analgesia at doses lower than those necessary to treat depression, they are effective against acute and experimental pain and they have fast onset times.
While the exact mechanisms contributing to the analgesic effects of these drugs has yet to be elucidated, it is thought that they act by inhibiting monoamine reuptake thereby elevating spinal levels of norepinephrine and serotonin. TCAs and SNRIs additionally act on other pain processing pathways, specifically they are noradrenergic α-, glutaminergic NMDA and histaminergic H1 receptor antagonists, they block sodium and calcium currents while promoting potassium flux, they boost GABAB function, weakly stimulate the opioid mu and delta receptors and reduces PGE2 and TNF production.
Reference
Verdu B et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68(18):
GABA = γ-aminobutyric acid; NDMA = N-methyl-D-aspartate; PGE = prostaglandin E; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; TNF = tumor necrosis factor
Verdu B et al. Drugs 2008; 68(18):

28. How Effective Are Antidepressants in the Management of Visceral Pain?
Studies are rare and data are controversial
Some studies have been conducted on healthy volunteers, which influences outcomes
Limited studies in patients suffering from visceral pain
In IBS patients, low dose amitriptyline (10 – 25 mg/day) for six weeks increased pressure thresholds needed to induce pain using rectal distension
Speaker’s Notes
References
Fioramonti J, Bueno L. Centrally acting agents and visceral sensitivity. Gut. 2002; 51(Suppl 1): i91–i95.
Some antidepressants increase pain threshold but have no effect on pain perception or discomfort
IBS = irritable bowel syndrome
Fioramonti J, Bueno L. Gut. 2002; 51(Suppl 1): i91–i95.

29. a2δ Ligands (Anticonvulsants) in the Management of Visceral Pain
Gabapentin
Pregabalin
Biochemically similar to GABA
MOA poorly understood
Binds to α2δ subunit of voltage-dependent calcium ion channel in CNS
May decrease Ca2+ influx into nerve terminal  affect release of multiple neurotransmitters, including substance P
Generally well tolerated
Dizziness, somnolence, and peripheral edema common
May increase pain threshold in IBS
Successor to gabapentin
Animal and human trials have demonstrated blunted visceral pain perception
One study in IBS patients showed an increase in sensory distension thresholds to normal levels and decreased pain
Speaker’s Notes
References
Lacy BE, Weiser K, De Lee R. The treatment of irritable bowel syndrome. Therap Adv Gastroenterol. 2009;2(4):
In theory, gabapentin and pregabalin may be helpful in the treatment of visceral pain.
However, little data currently supports their use and all use is considered off-label.
CNS = central nervous system; GABA = gamma-aminobutyric acid; IBS = irritable bowel syndrome; MOA = mechanism of action
Lacy BE et al. Therap Adv Gastroenterol. 2009;2(4):

30. 2 Ligands Reduce Calcium Influx in Depolarized Human Neocortex Synaptosomes
110
*p <0.05 vs. vehicle
100 90 *
Ca2+ fluorescence
(% of control) 80 * * * 70
Speaker’s Notes
Human neocortex tissue samples were obtained during surgery for epilepsy. Tissues were maintained in oxygenated saline solution, homogenized, and synaptosomes (small particles containing mostly synaptic endings) were isolated by differential centrifugation of chilled tissue homogenates. Calcium influx was measured by change in fluorescence of a calcium-sensitive dye.
Pregabalin pretreatment reduces the amount of calcium entering human neocortex synaptosomes in response to sustained depolarization (2-minute application of 30 mM potassium ions). The decrease in calcium influx by pregabalin was similar in magnitude to the decrease in neurotransmitter release (not shown) caused by pregabalin in the same preparation.
Reference
Fink K et al. Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacol 2002; 42(2): 60 50
Vehicle 10
100
1,000
Concentration (μM)
Fink K et al. Neuropharmacology 2002; 42(2):

31. 2 Ligands Modulate Calcium Channel Trafficking
100
**p <0.001
***p <0.01
Vehicle
10 mg/kg 2 ligand 80 60
% Increase in α2δ-1 40
*** ** 20
Speaker’s Notes
Increasing evidence suggest the analgesic effect of α2δ ligands is effected through modulation of calcium channel trafficking.
The left panel outlines the mechanism of action of gabapentin proposed by Hendrich and colleagues demonstrated that gabapentin based on their findings in in vitro studies. They posit that gabapentin binds to the α2δ subunit of certain voltage-gated calcium channel complexes, thus reducing trafficking of the complexes to the cell surface.
The diagram illustrates some of the various sites at which gabapentin (red circles) or the putative endogenous ligand (green circles) may act on α2δ subunits.
The right hand panel shows the up-regulating of a2d in the ipsilateral dorsal root ganglion axons of dorsal roots as compared with the contralateral side after nerve injury caused by saline injection (blue bars). It also shows that injection of pregabalin results in a much smaller increase in α2δ in the dorsal horn. This suggests that α2δ ligands prevent nerve-injury induced up-regulation of α2δ in the dorsal horn.
References
Bauer CS et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. Neurosci 2009; 29(13):
Hendrich J et al. Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proc Natl Acad Sci U S A 2008; 105(9): L4 L5 L6
Hendrich et al. 2008
Bauer et al. 2009
2 ligands reduce trafficking of voltage-gated calcium channel complexes to cell surface in vitro
2 ligands prevent nerve-injury induced up-regulation of a2d in the dorsal horn
BCH = 2-(−)-endoamino-bicycloheptene-2-carboxylic acid; ER = endoplasmic reticulum; GBP = gabapentin
Bauer CS et al. Neurosci 2009; 29(13): ; Hendrich J et al. Proc Natl Acad Sci U S A 2008; 105(9):

32. Multimodal or Balanced Analgesia
Opioid
Potentiation
Improved analgesia
 doses of each analgesic
 severity of side effects of each drug
Acetaminophen
nsNSAIDs/coxibs
α2δ ligands
Ketamine
Clonidine
Nerve blocks
Speaker’s Notes
Optimal pain management that allows a patient to lead a normal life is unlikely to be achieved with a single analgesic.
The concept of multimodal or balanced management pivots around the notion that by combining analgesics that work on distinct parts of the pain transmission circuit, pain management can be improved with lower doses of the individual analgesic and accordingly yield less side effects.
Reference
Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993; 77(5):
Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug
Kehlet H, Dahl JB. Anesth Analg 1993; 77(5):

33. Synergistic or Additive Effects of Analgesics Used in Combination
Agents with different MOAs can potentially have additive or synergistic effects:
Acetaminophen/NSAIDS + opioids
Opioids + local anesthetics
Centrally acting agents + NSAIDS
Opioids + 2δ ligands (e.g., dexamethatomidine)
Speaker’s Notes
Agents recommended for pain management stem from a multitude of drug classes and elicit their analgesic effects via different receptor and second messenger systems. From a pharmacological perspective, co-administration of analgesics that activate different molecular networks may not only result in additive/synergistic outcomes but may also result in less side effects and reliance on/addictiveness to one class of drugs.
References
Bader P et al. Guidelines on Pain Management. European Association of Urology; Arnhem, The Netherlands: 2010.
Kehlet H et al. Local infiltration analgesia in joint replacement: the evidence and recommendations for clinical practice. Acta Anaesthesiol Scand 2010; 55(7):
Paul S et al. Efficacy of intra-articular dexmedetomidine for postoperative analgesia in arthroscopic knee surgery. Ceylon Med J 2010; 55(4):111-5.
Robert B et al. The determination and application of fixed-dose analgesic combinations for treating multimodal pain. J Pain 2010; 11(8):701-9.
Starks I et al. Local anaesthetic infiltration in joint replacement surgery: what is its role in enhanced recovery? ISRN Anesthesiology 2011; 2011:
Vadivelu N et al. Recent advances in postoperative pain management. Yale J Biol Med 2010; 83(1):11-25.
MOA = mechanism of action; NSAID = non-steroidal anti-inflammatory drug
Bader P et al. Guidelines on Pain Management. European Association of Urology; Arnhem, The Netherlands: 2010; Kehlet H et al. Acta Anaesthesiol Scand 2010; 55(7):778-84; Paul S et al. Ceylon Med J 2010; 55(4):111-5; Robert B et al. J Pain 2010; 11(8):701-9; Starks I et al. ISRN Anesthesiology 2011; 2011:742927; Vadivelu N et al. Yale J Biol Med 2010; 83(1):11-25.

34. Spinal Cord Stimulation (SCS) and Visceral Pain
Used for >40 years to control complex intractable pain syndromes
Especially neuropathic pain
Precise mechanism of analgesia is unknown
Recent study (2015) showed SCS significantly reduced pain in IBS
Trend in reducing number of attacks, diarrheas
2014 study reported sacral nerve stimulation can significantly reduce symptoms and improve QoL of patients with IBS
SCS is a minimally invasive treatment option IBS pain
Can also be used for chronic pelvic pain
Speaker’s Notes
References
Hunter C, Davé N, Diwan S, Deer T. Neuromodulation of pelvic visceral pain: review of the literature and case series of potential novel targets for treatment. Pain Pract ;13(1):3-17.
Lind G, Winter J, Linderoth B, Hellstrom PM. Therapeutic value of spinal cord stimulation in irritable bowel syndrome – a randomized cross-over pilot study. Available at: Accessed March 25, 2015.
Abdel-Aziz S, Ghaleb A. Combined sacral nerve roots stimulation and low thoracic spinal cord stimulation for the treatment of chronic pelvic pain. Pain Studies Treatment ;2:86-90.
IBS = irritable bowel syndrome; QoL = quality of life
Hunter C et al. Pain Pract. 2013;13(1):3-17; Lind G et al. Therapeutic value of spinal cord stimulation in irritable bowel syndrome – a randomized cross-over pilot study. Available at: Accessed March 25, 2015; Abdel-Aziz S, Ghaleb A. Pain Studies Treatment. 2014;2:86-90.

35. Neuromodulation and Visceral Pain
Sacral nerve root stimulation effective in:
Interstitial cystitis
Painful bladder syndrome
Chronic prostatitis
Coccygodynia
Vulvodynia
Anorectal pain
Chronic pelvic pain
Bladder dysfunction, incontinence, urinary retention
Speaker’s Notes
Reference
Abdel-Aziz S, Ghaleb A. Combined sacral nerve roots stimulation and low thoracic spinal cord stimulation for the treatment of chronic pelvic pain. Pain Studies Treatment. 2014;2:86-90.
Abdel-Aziz S, Ghaleb A. Pain Studies Treatment. 2014;2:86-90.

36. Neuromodulation and Interstitial Cystitis (IC)
Percentage of patients with IC with ≥50% improvement
in symptoms with neuromodulation
Speaker’s Notes
Reference
Peters KM. Neuromodulation for the Treatment of Refractory Interstitial Cystitis. Rev Urol. 2002;4(Suppl 1):S36-S43.
Peters KM. Neuromodulation for the Treatment of Refractory Interstitial Cystitis. Rev Urol. 2002;4(Suppl 1):S36-S43.

37. Treatment Recommendations for Visceral Pain

38. Guidelines for the Management of Visceral Pain
No consensus treatment recommendations or guidelines exist for the general management of visceral pain
WHO analgesic ladder can be used as a guideline in managing pain
WHO approach may need to be combined with other treatment modalities
Speaker’s Notes
The WHO analgesic ladder is intended to be a guideline in structuring the use of analgesia in the pharmacological management of pain, and is not intended to be a rigid framework. The WHO approach to pain control may need to be combined with other treatment modalities. The type and intensity of the pain should first be evaluated. Then the drug can be matched to the pain intensity and other characteristics.
The use of analgesia should start at the step of the analgesic ladder appropriate for the severity of pain. It is not necessary to initiate therapy at Step 1 if the person is experiencing moderate to severe pain, patients with severe pain should have therapy initiated at Step 3.
The use of the ladder is reversed in situations of acute pain, starting at Step 3 and moving to Step 1 analgesics as recovery occurs.
REFERENCE

39. World Health Organization Analgesic Ladder
Speaker’s Notes
The WHO analgesic ladder is intended to be a guideline in structuring the use of analgesia in the pharmacological management of pain, and is not intended to be a rigid framework. The WHO approach to pain control may need to be combined with other treatment modalities. The type and intensity of the pain should first be evaluated. Then the drug can be matched to the pain intensity and other characteristics.
The use of analgesia should start at the step of the analgesic ladder appropriate for the severity of pain. It is not necessary to initiate therapy at Step 1 if the person is experiencing moderate to severe pain, patients with severe pain should have therapy initiated at Step 3.
The use of the ladder is reversed in situations of acute pain, starting at Step 3 and moving to Step 1 analgesics as recovery occurs.
REFERENCE

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