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Drugs able to prevent chronic pain
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Available online at www.sciencedirect.com
www.elsevier.com/locate/trap
Drugs able to prevent chronic pain Grisell Vargas-Schaffer, MDa,b,c,d a
Department of Anesthesiology, University of Montreal, Montréal, Canada Department of Pharmacology, University of Montreal, Montréal, Canada c Centre de Recherche du Centre Hospitalière Université de Montréal, CRCHUM d Anesthesiologist and Pain Management, CHUM Pain Center 3840 rue Saint-Urbain, Hôtel-Dieu CHUM, Pavillon Jean-Mance 2e étage Clinique antidouleur, Montréal, Québec, Canada H2W 1T8 b
article info
abstract
Keywords:
Using drugs that follow anatomical pathways and act on receptors to treat acute pain and
Acute pain
prevent its transformation into chronic pain is an appealing idea. The challenge consists of
Prevention
providing personalized treatment based on risk factors, pain and surgery type, and the type of
Chronic pain
rehabilitation program to minimize complications and optimize the pain treatment to prevent
Therapeutic patient education
chronic pain. Clinical practice has started to understand the pathophysiological mechanisms and various neurochemical receptors involved in the transformation of acute pain into chronic pain. Unfortunately, the clinical reality differs greatly from the theory and no studies based on medical evidence show that using drugs to prevent chronic pain is a real possibility, nor what kinds of pain can actually be prevented with the use of preventive drugs. This article examines what kinds of pain are most commonly referred to chronic pain centers, looks at which drugs can be used to prevent chronic pain, and aims to establish a preventive treatment algorithm based on the type of postoperative pain. There is growing interest in providing therapeutic patient education, which consists of health professionals transferring knowledge to patients. In the model proposed in this article, therapeutic patient education acts as a connecting thread to different factors and enables patients to become more responsible for and proactive in the healing process. Prevention should be comprehensive, and not just pharmacologic. & 2015 Elsevier Inc. All rights reserved.
Introduction Using drugs that follow anatomical pathways and act on receptors to treat acute pain and therefore prevent acute pain from becoming chronic pain is an idea that appeals to many physicians. The challenge is to not simply use a magic combination of drugs, but rather the right drugs to treat a specific type of pain and minimize complications. The ultimate goal is to optimize the pain treatment in the hope of preventing chronic pain. Chronic pain prevention can be based on Hippocrates' dictum “primum non nocere.” The first step in achieving this
E-mail address: [email protected] http://dx.doi.org/10.1053/j.trap.2015.10.003 1084-208X/& 2015 Elsevier Inc. All rights reserved.
is realizing and accepting that acute pain exists. With this in mind, the topic of prevention must be considered. In 1998, the World Health Organization1,2 stated that prevention “covers measures not only to prevent the occurrence of disease, such as risk factor reduction, but also to arrest its progress and reduce its consequences once established.” On the contrary, the World Organization of Family Doctors3,4 defined quaternary prevention as “an action taken to identify a patient at risk of overmedicalization, to protect him from new medical invasion, and to suggest to him interventions which are ethically acceptable.”
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Drugs able to prevent PHN
Clinical practice has started to understand the pathophysiological mechanisms and various neurochemical receptors involved in the transformation of acute pain into chronic pain. Unfortunately, the clinical reality differs greatly from the theory explained in numerous published articles, basic research, and animal research. No studies based on medical evidence show that using drugs to prevent chronic pain is a real possibility, nor what kinds of pain can actually be prevented with the use of preventive drugs, in the way that certain infectious diseases can be prevented with the use of vaccines. The most important result to date is that the more intense and prolonged an acute pain episode, the more likely it would lead to chronic pain. The scientific literature on drugs able to prevent chronic pain is numerous but often controversial. Some studies show positive results for certain drugs, others have no conclusive results, and several subtly suggest using the drugs that they tested. The first publication on this topic appeared in 1998 and was by Crombie et al.5 Since then, thousands of articles have been published with the aim of preventing chronic pain. This article has 2 parts. The first part examines what kinds of pain (potentially preventable) are most commonly referred to chronic pain centers. It then looks at which drugs can be used to prevent chronic pain. The second part aims to establish a preventive treatment algorithm based on the type of postoperative pain. The pain pathologies in which chronic pain prevention has been more widely studied are complex regional pain syndrome (CRPS), postherpetic neuralgia (PHN), and acute postoperative pain.
PHN is a painful condition. In some patients, the pain does not resolve when the rash heals, but rather continues for months or years. The pain associated with herpes zoster (HZ) has 3 phases. The first phase is an acute herpetic neuralgia that accompanies the rash and lasts for approximately 30 days after the onset of the rash. The second is a subacute herpetic neuralgia that lasts for 30-120 days after the onset of the rash. The third is a chronic PHN, defined as pain that persists for 120 days after the onset of rash.14 There is high-quality evidence stating that oral acyclovir does not significantly reduce the incidence of PHN. In addition, there is insufficient evidence to determine the effects of other antiviral treatments.15,16 The Centers for Disease Control and Prevention recommends a dose of the HZ vaccine for people aged 60 years and older.16 The HZ vaccine is safe and effective in reducing the incidence of HZ and PHN, as well as in attenuating the severity of HZ disease in older adults. The greatest benefit of the HZ vaccine is that it prevents chronic PHN, which can be extremely difficult to treat.14,17 Nevertheless, evidence that the vaccine can prevent chronic pain has not been clearly established yet. A better preventive treatment of chronic PHN could be to start in the acute phase with first-line treatments of gabapentinoids and topical lidocaine (patch 5%). Second-line treatments would then include weak opioid analgesics and tricyclic antidepressants (TCAs) if the pain is moderate to severe for the first 30 days after the rash. However, there is no published evidence to support this.
Drugs and supplements able to prevent CRPS
Drugs able to prevent postoperative pain
CRPS, previously known as reflex sympathetic dystrophy, is one of the most challenging chronic pain conditions. In 1994, the International Association for the Study of Pain introduced the term CRPS to describe a wide variety of posttraumatic neuropathic pain conditions of the limbs.6 Regarding preventive treatment, it is logical to believe that adequate pain treatment after a fracture can help prevent CRPS, but there is no published evidence to support this.
Vitamin C Although supplements are not considered drugs, vitamin C reduces lipid peroxidation, scavenges hydroxyl radicals, protects the capillary endothelium, inhibits vascular permeability, and reduces injury to skeletal muscle caused by compartment syndrome.7-9 Vitamin C also reduces the prevalence of CRPS in adults following trauma.7-13 The Mayo Clinic recommendation after a wrist fracture is more than 1000 mg/d for 45 days. The best preventive treatments for CRPS for subsequent broken limbs are therapeutic patient education (TPE) on the role of vitamin C, treatment with gabapentinoids, the use of regular analgesics when pain is mild to moderate, and early mobilization.
A publication by the International Association for the Study of Pain defines persistent postoperative pain as pain that develops after surgical intervention and lasts at least 2 months; other causes for the pain must be excluded, in particular pain from a condition preceding the surgery.18,19 The most frequent manifestation of neuropathic pain associated with postoperative pain is allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain).20 Preemptive analgesia is defined as an antinociceptive treatment that prevents the establishment of altered central processing of afferent input, which amplifies postoperative pain.21 The emphasis of preemptive analgesia is on the pathophysiological phenomenon that it should prevent altered sensory processing and its effectiveness has been demonstrated.22 To adequately treat chronic pain, we must know what type of pain is present and then start the appropriate treatment of each patient. Unfortunately, there are no epidemiologic studies that allow us to establish which kind of pain (nociceptive, neuropathic, or mixed) is the most frequent for different types of surgery. The drugs most commonly used to prevent postoperative pain are described briefly in the following section.
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Nonsteroidal anti-inflammatory drugs and acetaminophen Nonsteroidal anti-inflammatory drugs (NSAIDs) have a mechanism of action based on inhibition of the enzymes that synthesize prostaglandins and a variety of other peripheral and central mechanisms. NSAIDs have traditionally been used to relieve pain after minor surgery23 and to reduce the need for opioids. They should be used carefully with patients with renal impairment, hypertension, cardiac failure, platelet dysfunction, and asthma. The mechanism of action of acetaminophen is unclear, but it has been suggested that it acts on the serotonergic inhibitory descending pathway and the endogenous opioid pathway.24,25 Furthermore, its mechanism of action has been suggested to be associated with the peripheral cannabinoid system.26,27 Acetaminophen is considered to have a better safety profile compared with NSAIDs.24 The use of NSAIDs and acetaminophen as drugs that prevent chronic pain has not been reported in medical literature.
Local anesthetics Local anesthetics interrupt neural conduction by inhibiting the influx of sodium ions.28 Local anesthetics may be the most commonly used drugs to prevent and treat acute postoperative pain. They are employed to reduce the use of opioids and to prolong the action of opioids, and are the main drugs used in various locoregional anesthesia techniques.29-31
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Gabapentinoids Gabapentin and pregabalin are widely used in the treatment of neuropathic chronic pain, attesting to their efficacy. They act mainly on the α-2-δ-1 subunit of presynaptic calcium channels, inhibit neuronal calcium influx, and may prevent central sensitization. Gabapentin is used in postoperative pain.35 It has been shown that gabapentin-like compounds have low potency against acute pain but, in combination with opioids, they allow a reduction in opioid dose with improved analgesia.36 It is important to do a dosages adjustment for gabapentinoids in patients with renal impairment.
N-methyl-D-aspartate receptor antagonist The N-methyl-D-aspartate (NMDA) receptor is an excitatory amino acid receptor that has been implicated in the modulation of prolonged pain states in animal models and was used to treat postoperative pain.37,38 NMDA antagonists may reduce pain, opioid consumption, or both by 2 nonmutually exclusive mechanisms.38 However, the results regarding using them as drugs to prevent chronic pain remain controversial.
Alpha-2 agonists Alpha-2 adrenergic agonists have been useful as an adjuvant for regional analgesia and in the treatment of postoperative pain.39 Alpha-2 adrenergic agonists cause sedation, hypotension, and bradycardia in moderate doses, but in low doses they can be opioid sparing.
Antidepressant drugs The antidepressants most commonly used to treat pain are TCAs, and the primary mechanism by which TCAs relieve the symptoms of depressive illness and pain appears to involve the inhibition of neurotransmitter reuptake. TCAs have additional effects on a variety of ion channels. For example, TCAs block Na1 channels in cardiac tissues in a similar fashion to the action of local anesthetics.32 The preemptive administration of venlafaxine has been shown to be efficient in reducing the incidence of neuropathic pain in animal models. In the case of postmastectomy pain syndrome, 100 patients who were treated in the perioperative period with venlafaxine against placebo the night before surgery demonstrated a reduced incidence of postmastectomy pain syndrome following breast cancer surgery.33 To date, there have not been many randomized controlled trials examining the potential analgesic action of antidepressant drugs to prevent postoperative pain. Data from 41 controlled trials indicate that TCAs are effective analgesics. Amitriptyline is the most thoroughly studied agent in postoperative pain, but the results are controversial.34
Neostigmine Neostigmine is an anticholinesterase drug39 and can be used as a coanalgesic in postoperative pain treatment.40,41
Magnesium sulfate Magnesium sulfate is an inorganic salt; magnesium (Mg) is a noncompetitive NMDA receptor antagonist with antinociceptive effects. Magnesium is the second-most-abundant intracellular cation and is involved in the regulation of many ion channels and enzymatic reactions. Most studies suggest that perioperative magnesium sulfate reduces anesthetic requirements and improves postoperative analgesia. However, some studies have concluded that magnesium sulfate has limited or no effect.42,43 Studies by Levaux et al and Mentes et al support the idea of magnesium sulfate as a useful adjuvant for postoperative analgesia after major lumbar surgery, with an infusion of 50 mg kg(1) magnesium sulfate or an equivalent volume of saline at induction of anesthesia.42,43
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Opioids Opioids have played an important role in treating postoperative pain for many decades and are still widely used in clinical practice. However, the use of opioids to treat acute or chronic noncancer pain and cancer pain is founded on information gleaned after the first 10 years of dissemination and worldwide use of the analgesic ladder in 1986. Since then, numerous medical articles have been published promoting opioids as a safe treatment of patients with chronic noncancer pain. Weak opioids are recommended to treat moderate to severe pain and are as follows: tramadol, tapentadol, and buprenorphine. Strong opioids are recommended to treat severe pain and are as follows: morphine, oxycodone, hydromorphone, fentanyl, and methadone.44 Tramadol is a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. It has 2 different mechanisms. First, it binds to the m-opioid receptor (MOR). Second, it inhibits the reuptake of serotonin and norepinephrine. The analgesic efficacy and safety of tramadol has been demonstrated.45,46 Tramadol has been in clinical use in Germany since the late 1970s. Tapentadol combines a MOR agonist action and norepinephrine reuptake inhibition in a single molecule. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effects.47 Morphine is the most widely used and studied opioid.48 Oxycodone, a semisynthetic opioid synthesized from thebaine, is a m-opioid agonist. Its use in the prevention and treatment of acute postoperative pain is widely recognized.49-52 Hydromorphone, a semisynthetic opioid derivate of morphine, is a m-opioid agonist. Its use in postoperative pain treatment became common after the 1970s. Methadone, a synthetic opioid, has a m-opioid agonist action, monoaminergic activity, and NMDA receptor antagonist activity. They include methadone's long and variable half-life, the potential association between the use of methadone and QTc interval prolongation and cardiac arrhythmia, the risk of torsades de pointes, and the potential for drug interactions. There are no recommendations for methadone to be used to prevent chronic pain.
Cannabinoids Cannabinoids act by preventing the transmission of nociceptive messages on the periphery, in the spinal dorsal horn, and in the periaqueductal gray substance upstream and downstream. Cannabinoids act by inhibiting nociception messages. The medical use of cannabis is currently very trendy and Health Canada provides information concerning the use of cannabis and cannabinoids for medical purposes.53 There are only 4 published reports on the use of cannabinoids in postoperative pain.54-57 The conclusions from these studies were that cannabinoids (tetrahydrocannabinol, nabilone, or an oral cannabis extract containing a 2:1 ratio of tetrahydrocannabinol to cannabidiol) are not ideally suited to manage
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postoperative pain because they are either moderately effective or not different from placebo.
Therapeutic patient education (TPE) as a drug able to prevent chronic pain There is growing interest in providing educational programs for patients with chronic and acute diseases. TPE, a specific branch of health education, requires a continuous process of care and support. TPE was created as a response to the need for tertiary health care prevention and involves health professionals passing on some of their knowledge and expertise to the patient. Despite not being a drug itself, this method appears to greatly complement the prevention and treatment of chronic pain. According to a 1988 statement by the World Health Organization, TPE may be viewed as a set of structured activities that consists of “helping the patient and his family to acquire knowledge and competencies on the disease and its treatment, to collaborate better with the caregivers, and to improve his quality of life.” In our modern society, chronic pain should not be considered as a secondary symptom of another illness, but rather a chronic disease in and of itself. Under these circumstances, the key to successful treatment might lie in a paradigm in which patients are at the center of an individualized, multidisciplinary pain treatment strategy that both requires and empowers them to become dynamic participants in their care. Furthermore, they are actively supported in this endeavor through the provision of patient TPE.58
Intervention timeline to prevent chronic pain To conclude, a review is presented in Figure 1. The upper section shows the basic idea that acute pain can develop into chronic pain. However, not all patients develop chronic pain and the reasons behind this fact remain unclear. The lower section shows a model of evaluation and treatment to prevent acute pain from developing into chronic pain. TPE acts as a connecting thread to different factors, including evaluation and treatment of risk factors, type of surgery, and type of pain (neuropathic, nociceptive, mixed, pain at rest, motion pain, and pain associated with rehabilitation programs). Additionally, multimodal analgesia with different drugs and techniques for pre-, intra-, and postoperative treatment is also related to TPE with the purpose of adhering the patient to the treatment. Patients who are well informed and educated about the different techniques, drugs, and side effects of the treatment are more proactive and take charge of their recovery. This could decrease and prevent chronic pain that arises from acute pain.
Preventive treatment algorithm based on the type of pain Figure 2 illustrates the 3 types of postoperative pain and the drugs that can prevent them. Nociceptive pain can be treated with NSAIDs (for short periods of time to prevent complications), acetaminophen, weak opioids, and strong opioids
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Fig. 1 – Hypothetical model to explain the different factors to be taken into consideration to prevent the progression or transformation from acute to chronic pain. The central idea is placing the patient into a multidisciplinary, complementary, and integrative medicine approach, to maintain the patient as an active participant at the center of the pain management strategy through the therapeutic patient education. (when the pain is moderate to severe). Neuropathic pain can be treated with gabapentinoids, antidepressant drugs, topical treatments (lidocaine and capsaicin), NMDA receptor antagonists, alpha-2 agonists, neostigmine, and magnesium sulfate. Mixed pain can be treated with a combination of both categories. The latter is the most frequent type of pain found in pain centers and most cases are from postmastectomy, postthoracotomy, amputations, inguinal hernia, and abdominal surgery.
Perioperative management for chronic pain prevention The Table illustrates a proposal for preventive treatment of most types of chronic postoperative pain that are referred to pain centers. It is important to note that this type of pain management is aimed at patients who have a high risk of developing chronic pain.
Fig. 2 – The different types of postoperative pain and the drugs that can be used to prevent chronic pain.
Table – Perioperative management for chronic pain prevention. Preemptive analgesia
Postoperative pain most commonly referred to chronic pain centers Patients with a high risk of developing chronic postoperative pain
24/48 h before surgery Dosing the night before surgery Therapeutic patient education (TPE) Gabapentin 300 mg Pregabalin 50-100 mg Venlafaxine 37, 5 mg
Relief: pain in rehabilitation programs
Therapeutic patient education (TPE)
Therapeutic patient education (TPE)
RAT Patient-controlled analgesia (PCA) Venlafaxine 75 mg/d Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids for cancer pain; for severe pain use strong opioids RAT Patient-controlled analgesia (PCA)
Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d
Lidocaine IV NMDA receptor antagonist RAT
Lidocaine IV NMDA receptor antagonist RAT
Head and neck surgery
Gabapentin 300 mg
Lidocaine IV NMDA receptor antagonist
Pregabalin 50-100 mg Amitriptyline 25 mg
RAT Acetaminophen 3 g/d Gabapentin 600 mg/d Pregabalin 150 mg/d Patient-controlled analgesia (PCA)
Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids For severe pain, use strong opioids
Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d
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Gabapentin 300 mg Pregabalin 50-100 mg
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Abdominal hysterectomy and herniorrhaphy
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Pregabalin 50-100 mg
Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids For severe pain, use strong opioids Patient-controlled analgesia (PCA) Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids For severe pain, use strong opioids
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Lidocaine IV NMDA receptor antagonist
RAT patient-controlled analgesia (PCA)
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Pregabalin 50-100 mg Amitriptyline 25 mg Gabapentin 300 mg
Lidocaine IV NMDA receptor antagonist RAT
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Vitamin C more than 1000 mg Gabapentin 300 mg
Weak opioids; for severe pain use strong opioids
Pregabalin 300 mg or 4/d Venlafaxine 75-150 mg/d Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d
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Lumbar laminectomy and fusion
Relief: pain at rest and in motion
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Gabapentin 300 mg
Therapeutic patient education (TPE) Lidocaine IV NMDA receptor antagonist Regional anesthesia technics (RAT)
Pregabalin 50-100 mg
Limb fractures or total knee or hip arthroplasty
Analgesia 1-2 weeks after surgery
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Cardiac or coronary artery bypass or thoracic surgery
Postoperative pain, 24-72 h
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Breast surgery (including cancer, mastectomy, implants, flaps, and reconstruction)
Intraoperative treatment
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Amitriptyline 50-75 mg/d
IV, intravenously.
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It should also be noted that most publications that have examined postoperative pain treatments have been limited by a small sample size, limited follow-ups, varied surgical populations, and widely varying dosing regimens. The suggestions made in the Table are based on a summary of experiences in chronic postoperative pain management. Therefore, not observing an effect should not be construed as strong evidence that an effect does not exist. Optimal duration of treatment is unknown, but preventive treatment may be necessary for up to 2 weeks after surgery.
Conclusion The first step in solving any problem is recognizing that there is one. In our field of pain management, the first step is to recognize that acute pain exists; the second step is to provide personalized treatment based on risk factors, the type of pain and surgery, and the type of rehabilitation program; the third and final step is to involve the patient in the treatment to make him or her more responsible and proactive in the healing process. Unfortunately, to achieve adequate prevention of chronic pain with drugs only, there must be many studies based on each type of pain, not just general drug recipes. Prevention should be comprehensive, and not just pharmacologic.
r e f e r e n c e s
1. World Health Organization. Health Promotion Glossary. Geneva: Division of Health Promotion, Education and Communications (HPR) and Health Education and Promotion Unit (HEP); 1998. 2. Groene O, Garcia-Barbero M, et al., eds. Health Promotion in Hospitals: Evidence and Quality Management. Copenhagen: WHO Regional Office for Europe; 2005. 3. Bentzen N, ed. WONCA Dictionary of General/Family Practice. S.l.: WONCA International Classification Committee; 2003. 4. Starfield B, Hyde J, Gérvas J, et al. The concept of prevention: a good idea gone astray? J Epidemiol Community Health. 2008; 62(7):580–583. 5. Crombie IK, Davies HT, Macrae WA. Cut and thrust: antecedent surgery and trauma among patients attending a chronic pain clinic. Pain. 1998;76(1):167–171. 6. Classifications of chronic pain: description of chronic pain syndromes and definitions of pain termsIn: Merskey H, Bogduk N, et al., eds. Prepared by the Task Force on Taxonomy of the International Association for the Study of Pain. Seattle: IASP Press; 1994. 7. Zollinger PE, Tuinebreijer WE, Breederveld RS, et al. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am. 2007; 89(7):1424–1431. 8. Tanaka H, Matsuda T, Shimazaki S, et al. Vitamin C as a radical scavenger in the treatment of extensive burns. Int J Intens Care. 1999;6:146–152. 9. Kearns SR, Daly AF, Sheehan K, et al. Oral vitamin C reduces the injury to skeletal muscle caused by compartment syndrome. J Bone Joint Surg. 2004;86(6):906–911. 10. Rohekar S. Daily vitamin C prevented development of complex regional pain syndrome in adults with wrist fractures. Evid Based Med. 2008;13(2):48.
P
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18 (2014) 92–99
11. Tran DQH, Duong S, Bertini P, et al. Treatment of complex regional pain syndrome: a review of the evidence. Can J Anesth. 2010;57(2):149–166. 12. Besse JL, Gadeyne S, Galand-Desmé S, et al. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle Surg. 2009;15(4):179–182. 13. Shibuya N, Humphers JM, Agarwal MR, et al. Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery: systematic review and meta-analysis. J Foot Ankle Surg. 2013;52(1):62–66. 14. Dworkin RH, Schmader KE. Treatment and prevention of postherpetic neuralgia. Clin Infect Dis. 2003;36(7):877–882. 15. Antiviral treatment for preventing nerve pain after shingles (postherpetic neuralgia). Cochrane Database of Systematic Reviews. 2013. Available at: http://www.ncbi.nlm.nih.gov/pub medhealth/PMH0014191. 16. Fashner J, Bell AL. Herpes zoster and postherpetic neuralgia: prevention and management. Am Fam Physician. 2011;83(12): 1432–1437. 17. Shapiro M, Guenther L. Update on herpes zoster vaccination: a family practitioner’s guide. Can Fam Physician. 2011;57(10): 1127–1131. 18. Macrae WA, Davies HTO. Chronic postsurgical pain. In: Crombie IK, ed, Epidemiology of Pain. Seattle: IASP Press; 1999. 125–142. 19. Schug S, Pogatzki-Zahn E. Chronic pain after surgery or injury. Pain Clin Updates. 2011;19:1. 20. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. 2014;13(9):924–935. 21. Kissin I. Preemptive analgesia. Anesthesiology. 2000;93(4): 1138–1143. 22. Ong CK, Lirk P, Seymour RA, et al. The efficacy of preemptive analgesia for acute postoperative pain management: A metaanalysis. Anesth Analg. 2005;100(3):757–773. 23. Murphy DF. NSAIDs and postoperative pain: sooner is better than later. Br Med J. 1993;306:1493–1494. 24. Argoff C. Mechanisms of pain transmission and pharmacologic management. Curr Med Res Opin. 2011;27(10):2019–2031. 25. Roca-Vinardell A, Ortega-Alvaro A, Gibert-Rahola J, et al. The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen. Anesthesiology. 2003;98(3):741–747. 26. Dani M, Guindon J, Lambert C, et al. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol. 2007;573(1–3): 214–215. 27. Mallet C, Daulhac L, Bonnefont J, et al. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain. 2008;139(1):190–200. 28. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53(3):98–109. 29. Goldstein A, Grimault P, Henique A, et al. Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: a placebo-controlled comparison of bupivacaine and ropivacaine. Anesth Analg. 2000;91(2): 403–407. 30. Barreveld A, Witte J, Chahal H, et al. Preventive analgesia by local anesthetics. Anesth Analg. 2013;116(5):1141–1161. 31. Eroglu A, Erturk E, Apan A, et al. Regional anesthesia for postoperative pain control. Biomed Res Int. 2014;2014:1–2. 32. Pancrazio JJ, Kamatchi GL, Roscoe AK, et al. Inhibition of neuronal Naþ channels by antidepressant drugs. J Pharmacol Exp Ther. 1998;284(1):208–214. 33. Reuben SS, Makari-Judson G, Lurie SD. Evaluation of efficacy of the perioperative administration of venlafaxine X R in the prevention of postmastectomy pain syndrome. J Pain Symptom Manage. 2004;27(2):133–139.
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34. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1): 30–36. 35. Dirks J, Fredensborg BB, Christensen D, et al. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology. 2002;97(3):560–564. 36. Fassoulaki A, Triga A, Melemeni A, et al. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg. 2005;101:1427–1432. 37. Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-Daspartate receptor for chronic pain management. J Pain Symptom Manage. 2000;20(5):358–373. 38. McCartney C, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg. 2004:1385–1400. 39. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5): 588–593. 40. Habib AS, Gan TJ. Use of neostigmine in the management of acute postoperative pain and labour pain. CNS Drugs. 2006;20(10): 821–839. 41. Abdulatif M, El-Sanabary M. Caudal neostigmine, bupivacaine, and their combination for postoperative pain management after hypospadias surgery in children. Anesth Analg. 2002;95(5):1215–1218. 42. Levaux CH, Bonhomme V, Dewandre PY, et al. Effect of intraoperative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia. 2003;58(2):131–135. 43. Mentes O, Harlak A, Yigit T, et al. Effect of intraoperative magnesium sulphate infusion on pain relief after laparoscopic cholecystectomy. Acta Anaesthesiol Scand. 2008;52(10): 1353–1359. 44. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56: 514–517. 45. Houmes RJ, Voets MA, Verkaaik A, et al. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg. 1992;74(4):510–514.
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46. Scott LJ, Perry CM. Tramadol. Drugs. 2000;60(1):139–176. 47. Raffa RB, Buschmann H, Christoph T, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 2012;13(10):1437–1449. 48. Stenseth K, Sellevold O, Breivik H. Epidural morphine for postoperative pain: experience with 1085 patients. Acta Anaesthesiol Scand. 1985;29(1):148–156. 49. Kokki H, Kokki M, Sjövall S. Oxycodone for the treatment of postoperative pain. Expert Opin Pharmacother. 2012;13(7): 1045–1058. 50. Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97(2):534–540. 51. Gaskell H, Derry S, Moore RA, et al. Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009;3: CD002763. http://dx.doi.org/10.1002/14651858.cd002763.pub2. 52. Lim B, Thong SY, Zhu HB, et al. Pre-medication with controlled-release oxycodone in the management of postoperative pain after ambulatory laparoscopic gynaecological surgery. OA Case Rep. 2013;2(4):40. 53. Information for Health Care Professionals. Cannabis (marihuana, marijuana) and the cannabinoids Health Canada, 2013. Available at: http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/ infoprof-eng.phptphp. 54. Holdcroft A, Maze M, Dore C, et al. A multicenter doseescalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104(5):1040–1046. 55. Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol. 1981;21(S1):320S–326S. 56. Buggy DJ, Toogood L, Maric S, et al. Lack of analgesic efficacy of oral δ-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1):169–172. 57. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anesth. 2006;53(8):769–775. 58. Vargas-Schaffer G, Cogan J. Patient therapeutic education: placing the patient at the centre of the WHO analgesic ladder. Can Fam Physician. 2014;60(3):234–241.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/trap
Drugs able to prevent chronic pain Grisell Vargas-Schaffer, MDa,b,c,d a
Department of Anesthesiology, University of Montreal, Montréal, Canada Department of Pharmacology, University of Montreal, Montréal, Canada c Centre de Recherche du Centre Hospitalière Université de Montréal, CRCHUM d Anesthesiologist and Pain Management, CHUM Pain Center 3840 rue Saint-Urbain, Hôtel-Dieu CHUM, Pavillon Jean-Mance 2e étage Clinique antidouleur, Montréal, Québec, Canada H2W 1T8 b
article info
abstract
Keywords:
Using drugs that follow anatomical pathways and act on receptors to treat acute pain and
Acute pain
prevent its transformation into chronic pain is an appealing idea. The challenge consists of
Prevention
providing personalized treatment based on risk factors, pain and surgery type, and the type of
Chronic pain
rehabilitation program to minimize complications and optimize the pain treatment to prevent
Therapeutic patient education
chronic pain. Clinical practice has started to understand the pathophysiological mechanisms and various neurochemical receptors involved in the transformation of acute pain into chronic pain. Unfortunately, the clinical reality differs greatly from the theory and no studies based on medical evidence show that using drugs to prevent chronic pain is a real possibility, nor what kinds of pain can actually be prevented with the use of preventive drugs. This article examines what kinds of pain are most commonly referred to chronic pain centers, looks at which drugs can be used to prevent chronic pain, and aims to establish a preventive treatment algorithm based on the type of postoperative pain. There is growing interest in providing therapeutic patient education, which consists of health professionals transferring knowledge to patients. In the model proposed in this article, therapeutic patient education acts as a connecting thread to different factors and enables patients to become more responsible for and proactive in the healing process. Prevention should be comprehensive, and not just pharmacologic. & 2015 Elsevier Inc. All rights reserved.
Introduction Using drugs that follow anatomical pathways and act on receptors to treat acute pain and therefore prevent acute pain from becoming chronic pain is an idea that appeals to many physicians. The challenge is to not simply use a magic combination of drugs, but rather the right drugs to treat a specific type of pain and minimize complications. The ultimate goal is to optimize the pain treatment in the hope of preventing chronic pain. Chronic pain prevention can be based on Hippocrates' dictum “primum non nocere.” The first step in achieving this
E-mail address: [email protected] http://dx.doi.org/10.1053/j.trap.2015.10.003 1084-208X/& 2015 Elsevier Inc. All rights reserved.
is realizing and accepting that acute pain exists. With this in mind, the topic of prevention must be considered. In 1998, the World Health Organization1,2 stated that prevention “covers measures not only to prevent the occurrence of disease, such as risk factor reduction, but also to arrest its progress and reduce its consequences once established.” On the contrary, the World Organization of Family Doctors3,4 defined quaternary prevention as “an action taken to identify a patient at risk of overmedicalization, to protect him from new medical invasion, and to suggest to him interventions which are ethically acceptable.”
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Drugs able to prevent PHN
Clinical practice has started to understand the pathophysiological mechanisms and various neurochemical receptors involved in the transformation of acute pain into chronic pain. Unfortunately, the clinical reality differs greatly from the theory explained in numerous published articles, basic research, and animal research. No studies based on medical evidence show that using drugs to prevent chronic pain is a real possibility, nor what kinds of pain can actually be prevented with the use of preventive drugs, in the way that certain infectious diseases can be prevented with the use of vaccines. The most important result to date is that the more intense and prolonged an acute pain episode, the more likely it would lead to chronic pain. The scientific literature on drugs able to prevent chronic pain is numerous but often controversial. Some studies show positive results for certain drugs, others have no conclusive results, and several subtly suggest using the drugs that they tested. The first publication on this topic appeared in 1998 and was by Crombie et al.5 Since then, thousands of articles have been published with the aim of preventing chronic pain. This article has 2 parts. The first part examines what kinds of pain (potentially preventable) are most commonly referred to chronic pain centers. It then looks at which drugs can be used to prevent chronic pain. The second part aims to establish a preventive treatment algorithm based on the type of postoperative pain. The pain pathologies in which chronic pain prevention has been more widely studied are complex regional pain syndrome (CRPS), postherpetic neuralgia (PHN), and acute postoperative pain.
PHN is a painful condition. In some patients, the pain does not resolve when the rash heals, but rather continues for months or years. The pain associated with herpes zoster (HZ) has 3 phases. The first phase is an acute herpetic neuralgia that accompanies the rash and lasts for approximately 30 days after the onset of the rash. The second is a subacute herpetic neuralgia that lasts for 30-120 days after the onset of the rash. The third is a chronic PHN, defined as pain that persists for 120 days after the onset of rash.14 There is high-quality evidence stating that oral acyclovir does not significantly reduce the incidence of PHN. In addition, there is insufficient evidence to determine the effects of other antiviral treatments.15,16 The Centers for Disease Control and Prevention recommends a dose of the HZ vaccine for people aged 60 years and older.16 The HZ vaccine is safe and effective in reducing the incidence of HZ and PHN, as well as in attenuating the severity of HZ disease in older adults. The greatest benefit of the HZ vaccine is that it prevents chronic PHN, which can be extremely difficult to treat.14,17 Nevertheless, evidence that the vaccine can prevent chronic pain has not been clearly established yet. A better preventive treatment of chronic PHN could be to start in the acute phase with first-line treatments of gabapentinoids and topical lidocaine (patch 5%). Second-line treatments would then include weak opioid analgesics and tricyclic antidepressants (TCAs) if the pain is moderate to severe for the first 30 days after the rash. However, there is no published evidence to support this.
Drugs and supplements able to prevent CRPS
Drugs able to prevent postoperative pain
CRPS, previously known as reflex sympathetic dystrophy, is one of the most challenging chronic pain conditions. In 1994, the International Association for the Study of Pain introduced the term CRPS to describe a wide variety of posttraumatic neuropathic pain conditions of the limbs.6 Regarding preventive treatment, it is logical to believe that adequate pain treatment after a fracture can help prevent CRPS, but there is no published evidence to support this.
Vitamin C Although supplements are not considered drugs, vitamin C reduces lipid peroxidation, scavenges hydroxyl radicals, protects the capillary endothelium, inhibits vascular permeability, and reduces injury to skeletal muscle caused by compartment syndrome.7-9 Vitamin C also reduces the prevalence of CRPS in adults following trauma.7-13 The Mayo Clinic recommendation after a wrist fracture is more than 1000 mg/d for 45 days. The best preventive treatments for CRPS for subsequent broken limbs are therapeutic patient education (TPE) on the role of vitamin C, treatment with gabapentinoids, the use of regular analgesics when pain is mild to moderate, and early mobilization.
A publication by the International Association for the Study of Pain defines persistent postoperative pain as pain that develops after surgical intervention and lasts at least 2 months; other causes for the pain must be excluded, in particular pain from a condition preceding the surgery.18,19 The most frequent manifestation of neuropathic pain associated with postoperative pain is allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain).20 Preemptive analgesia is defined as an antinociceptive treatment that prevents the establishment of altered central processing of afferent input, which amplifies postoperative pain.21 The emphasis of preemptive analgesia is on the pathophysiological phenomenon that it should prevent altered sensory processing and its effectiveness has been demonstrated.22 To adequately treat chronic pain, we must know what type of pain is present and then start the appropriate treatment of each patient. Unfortunately, there are no epidemiologic studies that allow us to establish which kind of pain (nociceptive, neuropathic, or mixed) is the most frequent for different types of surgery. The drugs most commonly used to prevent postoperative pain are described briefly in the following section.
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Nonsteroidal anti-inflammatory drugs and acetaminophen Nonsteroidal anti-inflammatory drugs (NSAIDs) have a mechanism of action based on inhibition of the enzymes that synthesize prostaglandins and a variety of other peripheral and central mechanisms. NSAIDs have traditionally been used to relieve pain after minor surgery23 and to reduce the need for opioids. They should be used carefully with patients with renal impairment, hypertension, cardiac failure, platelet dysfunction, and asthma. The mechanism of action of acetaminophen is unclear, but it has been suggested that it acts on the serotonergic inhibitory descending pathway and the endogenous opioid pathway.24,25 Furthermore, its mechanism of action has been suggested to be associated with the peripheral cannabinoid system.26,27 Acetaminophen is considered to have a better safety profile compared with NSAIDs.24 The use of NSAIDs and acetaminophen as drugs that prevent chronic pain has not been reported in medical literature.
Local anesthetics Local anesthetics interrupt neural conduction by inhibiting the influx of sodium ions.28 Local anesthetics may be the most commonly used drugs to prevent and treat acute postoperative pain. They are employed to reduce the use of opioids and to prolong the action of opioids, and are the main drugs used in various locoregional anesthesia techniques.29-31
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Gabapentinoids Gabapentin and pregabalin are widely used in the treatment of neuropathic chronic pain, attesting to their efficacy. They act mainly on the α-2-δ-1 subunit of presynaptic calcium channels, inhibit neuronal calcium influx, and may prevent central sensitization. Gabapentin is used in postoperative pain.35 It has been shown that gabapentin-like compounds have low potency against acute pain but, in combination with opioids, they allow a reduction in opioid dose with improved analgesia.36 It is important to do a dosages adjustment for gabapentinoids in patients with renal impairment.
N-methyl-D-aspartate receptor antagonist The N-methyl-D-aspartate (NMDA) receptor is an excitatory amino acid receptor that has been implicated in the modulation of prolonged pain states in animal models and was used to treat postoperative pain.37,38 NMDA antagonists may reduce pain, opioid consumption, or both by 2 nonmutually exclusive mechanisms.38 However, the results regarding using them as drugs to prevent chronic pain remain controversial.
Alpha-2 agonists Alpha-2 adrenergic agonists have been useful as an adjuvant for regional analgesia and in the treatment of postoperative pain.39 Alpha-2 adrenergic agonists cause sedation, hypotension, and bradycardia in moderate doses, but in low doses they can be opioid sparing.
Antidepressant drugs The antidepressants most commonly used to treat pain are TCAs, and the primary mechanism by which TCAs relieve the symptoms of depressive illness and pain appears to involve the inhibition of neurotransmitter reuptake. TCAs have additional effects on a variety of ion channels. For example, TCAs block Na1 channels in cardiac tissues in a similar fashion to the action of local anesthetics.32 The preemptive administration of venlafaxine has been shown to be efficient in reducing the incidence of neuropathic pain in animal models. In the case of postmastectomy pain syndrome, 100 patients who were treated in the perioperative period with venlafaxine against placebo the night before surgery demonstrated a reduced incidence of postmastectomy pain syndrome following breast cancer surgery.33 To date, there have not been many randomized controlled trials examining the potential analgesic action of antidepressant drugs to prevent postoperative pain. Data from 41 controlled trials indicate that TCAs are effective analgesics. Amitriptyline is the most thoroughly studied agent in postoperative pain, but the results are controversial.34
Neostigmine Neostigmine is an anticholinesterase drug39 and can be used as a coanalgesic in postoperative pain treatment.40,41
Magnesium sulfate Magnesium sulfate is an inorganic salt; magnesium (Mg) is a noncompetitive NMDA receptor antagonist with antinociceptive effects. Magnesium is the second-most-abundant intracellular cation and is involved in the regulation of many ion channels and enzymatic reactions. Most studies suggest that perioperative magnesium sulfate reduces anesthetic requirements and improves postoperative analgesia. However, some studies have concluded that magnesium sulfate has limited or no effect.42,43 Studies by Levaux et al and Mentes et al support the idea of magnesium sulfate as a useful adjuvant for postoperative analgesia after major lumbar surgery, with an infusion of 50 mg kg(1) magnesium sulfate or an equivalent volume of saline at induction of anesthesia.42,43
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Opioids Opioids have played an important role in treating postoperative pain for many decades and are still widely used in clinical practice. However, the use of opioids to treat acute or chronic noncancer pain and cancer pain is founded on information gleaned after the first 10 years of dissemination and worldwide use of the analgesic ladder in 1986. Since then, numerous medical articles have been published promoting opioids as a safe treatment of patients with chronic noncancer pain. Weak opioids are recommended to treat moderate to severe pain and are as follows: tramadol, tapentadol, and buprenorphine. Strong opioids are recommended to treat severe pain and are as follows: morphine, oxycodone, hydromorphone, fentanyl, and methadone.44 Tramadol is a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. It has 2 different mechanisms. First, it binds to the m-opioid receptor (MOR). Second, it inhibits the reuptake of serotonin and norepinephrine. The analgesic efficacy and safety of tramadol has been demonstrated.45,46 Tramadol has been in clinical use in Germany since the late 1970s. Tapentadol combines a MOR agonist action and norepinephrine reuptake inhibition in a single molecule. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effects.47 Morphine is the most widely used and studied opioid.48 Oxycodone, a semisynthetic opioid synthesized from thebaine, is a m-opioid agonist. Its use in the prevention and treatment of acute postoperative pain is widely recognized.49-52 Hydromorphone, a semisynthetic opioid derivate of morphine, is a m-opioid agonist. Its use in postoperative pain treatment became common after the 1970s. Methadone, a synthetic opioid, has a m-opioid agonist action, monoaminergic activity, and NMDA receptor antagonist activity. They include methadone's long and variable half-life, the potential association between the use of methadone and QTc interval prolongation and cardiac arrhythmia, the risk of torsades de pointes, and the potential for drug interactions. There are no recommendations for methadone to be used to prevent chronic pain.
Cannabinoids Cannabinoids act by preventing the transmission of nociceptive messages on the periphery, in the spinal dorsal horn, and in the periaqueductal gray substance upstream and downstream. Cannabinoids act by inhibiting nociception messages. The medical use of cannabis is currently very trendy and Health Canada provides information concerning the use of cannabis and cannabinoids for medical purposes.53 There are only 4 published reports on the use of cannabinoids in postoperative pain.54-57 The conclusions from these studies were that cannabinoids (tetrahydrocannabinol, nabilone, or an oral cannabis extract containing a 2:1 ratio of tetrahydrocannabinol to cannabidiol) are not ideally suited to manage
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postoperative pain because they are either moderately effective or not different from placebo.
Therapeutic patient education (TPE) as a drug able to prevent chronic pain There is growing interest in providing educational programs for patients with chronic and acute diseases. TPE, a specific branch of health education, requires a continuous process of care and support. TPE was created as a response to the need for tertiary health care prevention and involves health professionals passing on some of their knowledge and expertise to the patient. Despite not being a drug itself, this method appears to greatly complement the prevention and treatment of chronic pain. According to a 1988 statement by the World Health Organization, TPE may be viewed as a set of structured activities that consists of “helping the patient and his family to acquire knowledge and competencies on the disease and its treatment, to collaborate better with the caregivers, and to improve his quality of life.” In our modern society, chronic pain should not be considered as a secondary symptom of another illness, but rather a chronic disease in and of itself. Under these circumstances, the key to successful treatment might lie in a paradigm in which patients are at the center of an individualized, multidisciplinary pain treatment strategy that both requires and empowers them to become dynamic participants in their care. Furthermore, they are actively supported in this endeavor through the provision of patient TPE.58
Intervention timeline to prevent chronic pain To conclude, a review is presented in Figure 1. The upper section shows the basic idea that acute pain can develop into chronic pain. However, not all patients develop chronic pain and the reasons behind this fact remain unclear. The lower section shows a model of evaluation and treatment to prevent acute pain from developing into chronic pain. TPE acts as a connecting thread to different factors, including evaluation and treatment of risk factors, type of surgery, and type of pain (neuropathic, nociceptive, mixed, pain at rest, motion pain, and pain associated with rehabilitation programs). Additionally, multimodal analgesia with different drugs and techniques for pre-, intra-, and postoperative treatment is also related to TPE with the purpose of adhering the patient to the treatment. Patients who are well informed and educated about the different techniques, drugs, and side effects of the treatment are more proactive and take charge of their recovery. This could decrease and prevent chronic pain that arises from acute pain.
Preventive treatment algorithm based on the type of pain Figure 2 illustrates the 3 types of postoperative pain and the drugs that can prevent them. Nociceptive pain can be treated with NSAIDs (for short periods of time to prevent complications), acetaminophen, weak opioids, and strong opioids
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Fig. 1 – Hypothetical model to explain the different factors to be taken into consideration to prevent the progression or transformation from acute to chronic pain. The central idea is placing the patient into a multidisciplinary, complementary, and integrative medicine approach, to maintain the patient as an active participant at the center of the pain management strategy through the therapeutic patient education. (when the pain is moderate to severe). Neuropathic pain can be treated with gabapentinoids, antidepressant drugs, topical treatments (lidocaine and capsaicin), NMDA receptor antagonists, alpha-2 agonists, neostigmine, and magnesium sulfate. Mixed pain can be treated with a combination of both categories. The latter is the most frequent type of pain found in pain centers and most cases are from postmastectomy, postthoracotomy, amputations, inguinal hernia, and abdominal surgery.
Perioperative management for chronic pain prevention The Table illustrates a proposal for preventive treatment of most types of chronic postoperative pain that are referred to pain centers. It is important to note that this type of pain management is aimed at patients who have a high risk of developing chronic pain.
Fig. 2 – The different types of postoperative pain and the drugs that can be used to prevent chronic pain.
Table – Perioperative management for chronic pain prevention. Preemptive analgesia
Postoperative pain most commonly referred to chronic pain centers Patients with a high risk of developing chronic postoperative pain
24/48 h before surgery Dosing the night before surgery Therapeutic patient education (TPE) Gabapentin 300 mg Pregabalin 50-100 mg Venlafaxine 37, 5 mg
Relief: pain in rehabilitation programs
Therapeutic patient education (TPE)
Therapeutic patient education (TPE)
RAT Patient-controlled analgesia (PCA) Venlafaxine 75 mg/d Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids for cancer pain; for severe pain use strong opioids RAT Patient-controlled analgesia (PCA)
Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d
Lidocaine IV NMDA receptor antagonist RAT
Lidocaine IV NMDA receptor antagonist RAT
Head and neck surgery
Gabapentin 300 mg
Lidocaine IV NMDA receptor antagonist
Pregabalin 50-100 mg Amitriptyline 25 mg
RAT Acetaminophen 3 g/d Gabapentin 600 mg/d Pregabalin 150 mg/d Patient-controlled analgesia (PCA)
Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids For severe pain, use strong opioids
Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d
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Gabapentin 300 mg Pregabalin 50-100 mg
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Abdominal hysterectomy and herniorrhaphy
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Pregabalin 50-100 mg
Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids For severe pain, use strong opioids Patient-controlled analgesia (PCA) Gabapentin 600 mg/d Pregabalin 150 mg/d Weak opioids For severe pain, use strong opioids
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Lidocaine IV NMDA receptor antagonist
RAT patient-controlled analgesia (PCA)
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Pregabalin 50-100 mg Amitriptyline 25 mg Gabapentin 300 mg
Lidocaine IV NMDA receptor antagonist RAT
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Vitamin C more than 1000 mg Gabapentin 300 mg
Weak opioids; for severe pain use strong opioids
Pregabalin 300 mg or 4/d Venlafaxine 75-150 mg/d Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d Strong opioids if pain is not controlled with weak opioids Privileging long action Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d Gabapentin 900 mg or 4/d Pregabalin 300 mg or 4/d Amitriptyline 50-75 mg/d
AN
Lumbar laminectomy and fusion
Relief: pain at rest and in motion
E G I O N A L
Gabapentin 300 mg
Therapeutic patient education (TPE) Lidocaine IV NMDA receptor antagonist Regional anesthesia technics (RAT)
Pregabalin 50-100 mg
Limb fractures or total knee or hip arthroplasty
Analgesia 1-2 weeks after surgery
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Cardiac or coronary artery bypass or thoracic surgery
Postoperative pain, 24-72 h
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Breast surgery (including cancer, mastectomy, implants, flaps, and reconstruction)
Intraoperative treatment
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Type of surgery
Amitriptyline 50-75 mg/d
IV, intravenously.
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It should also be noted that most publications that have examined postoperative pain treatments have been limited by a small sample size, limited follow-ups, varied surgical populations, and widely varying dosing regimens. The suggestions made in the Table are based on a summary of experiences in chronic postoperative pain management. Therefore, not observing an effect should not be construed as strong evidence that an effect does not exist. Optimal duration of treatment is unknown, but preventive treatment may be necessary for up to 2 weeks after surgery.
Conclusion The first step in solving any problem is recognizing that there is one. In our field of pain management, the first step is to recognize that acute pain exists; the second step is to provide personalized treatment based on risk factors, the type of pain and surgery, and the type of rehabilitation program; the third and final step is to involve the patient in the treatment to make him or her more responsible and proactive in the healing process. Unfortunately, to achieve adequate prevention of chronic pain with drugs only, there must be many studies based on each type of pain, not just general drug recipes. Prevention should be comprehensive, and not just pharmacologic.
r e f e r e n c e s
1. World Health Organization. Health Promotion Glossary. Geneva: Division of Health Promotion, Education and Communications (HPR) and Health Education and Promotion Unit (HEP); 1998. 2. Groene O, Garcia-Barbero M, et al., eds. Health Promotion in Hospitals: Evidence and Quality Management. Copenhagen: WHO Regional Office for Europe; 2005. 3. Bentzen N, ed. WONCA Dictionary of General/Family Practice. S.l.: WONCA International Classification Committee; 2003. 4. Starfield B, Hyde J, Gérvas J, et al. The concept of prevention: a good idea gone astray? J Epidemiol Community Health. 2008; 62(7):580–583. 5. Crombie IK, Davies HT, Macrae WA. Cut and thrust: antecedent surgery and trauma among patients attending a chronic pain clinic. Pain. 1998;76(1):167–171. 6. Classifications of chronic pain: description of chronic pain syndromes and definitions of pain termsIn: Merskey H, Bogduk N, et al., eds. Prepared by the Task Force on Taxonomy of the International Association for the Study of Pain. Seattle: IASP Press; 1994. 7. Zollinger PE, Tuinebreijer WE, Breederveld RS, et al. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am. 2007; 89(7):1424–1431. 8. Tanaka H, Matsuda T, Shimazaki S, et al. Vitamin C as a radical scavenger in the treatment of extensive burns. Int J Intens Care. 1999;6:146–152. 9. Kearns SR, Daly AF, Sheehan K, et al. Oral vitamin C reduces the injury to skeletal muscle caused by compartment syndrome. J Bone Joint Surg. 2004;86(6):906–911. 10. Rohekar S. Daily vitamin C prevented development of complex regional pain syndrome in adults with wrist fractures. Evid Based Med. 2008;13(2):48.
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18 (2014) 92–99
11. Tran DQH, Duong S, Bertini P, et al. Treatment of complex regional pain syndrome: a review of the evidence. Can J Anesth. 2010;57(2):149–166. 12. Besse JL, Gadeyne S, Galand-Desmé S, et al. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle Surg. 2009;15(4):179–182. 13. Shibuya N, Humphers JM, Agarwal MR, et al. Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery: systematic review and meta-analysis. J Foot Ankle Surg. 2013;52(1):62–66. 14. Dworkin RH, Schmader KE. Treatment and prevention of postherpetic neuralgia. Clin Infect Dis. 2003;36(7):877–882. 15. Antiviral treatment for preventing nerve pain after shingles (postherpetic neuralgia). Cochrane Database of Systematic Reviews. 2013. Available at: http://www.ncbi.nlm.nih.gov/pub medhealth/PMH0014191. 16. Fashner J, Bell AL. Herpes zoster and postherpetic neuralgia: prevention and management. Am Fam Physician. 2011;83(12): 1432–1437. 17. Shapiro M, Guenther L. Update on herpes zoster vaccination: a family practitioner’s guide. Can Fam Physician. 2011;57(10): 1127–1131. 18. Macrae WA, Davies HTO. Chronic postsurgical pain. In: Crombie IK, ed, Epidemiology of Pain. Seattle: IASP Press; 1999. 125–142. 19. Schug S, Pogatzki-Zahn E. Chronic pain after surgery or injury. Pain Clin Updates. 2011;19:1. 20. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. 2014;13(9):924–935. 21. Kissin I. Preemptive analgesia. Anesthesiology. 2000;93(4): 1138–1143. 22. Ong CK, Lirk P, Seymour RA, et al. The efficacy of preemptive analgesia for acute postoperative pain management: A metaanalysis. Anesth Analg. 2005;100(3):757–773. 23. Murphy DF. NSAIDs and postoperative pain: sooner is better than later. Br Med J. 1993;306:1493–1494. 24. Argoff C. Mechanisms of pain transmission and pharmacologic management. Curr Med Res Opin. 2011;27(10):2019–2031. 25. Roca-Vinardell A, Ortega-Alvaro A, Gibert-Rahola J, et al. The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen. Anesthesiology. 2003;98(3):741–747. 26. Dani M, Guindon J, Lambert C, et al. The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol. 2007;573(1–3): 214–215. 27. Mallet C, Daulhac L, Bonnefont J, et al. Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain. 2008;139(1):190–200. 28. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53(3):98–109. 29. Goldstein A, Grimault P, Henique A, et al. Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: a placebo-controlled comparison of bupivacaine and ropivacaine. Anesth Analg. 2000;91(2): 403–407. 30. Barreveld A, Witte J, Chahal H, et al. Preventive analgesia by local anesthetics. Anesth Analg. 2013;116(5):1141–1161. 31. Eroglu A, Erturk E, Apan A, et al. Regional anesthesia for postoperative pain control. Biomed Res Int. 2014;2014:1–2. 32. Pancrazio JJ, Kamatchi GL, Roscoe AK, et al. Inhibition of neuronal Naþ channels by antidepressant drugs. J Pharmacol Exp Ther. 1998;284(1):208–214. 33. Reuben SS, Makari-Judson G, Lurie SD. Evaluation of efficacy of the perioperative administration of venlafaxine X R in the prevention of postmastectomy pain syndrome. J Pain Symptom Manage. 2004;27(2):133–139.
T
E C H N I Q U E S I N
R
E G I O N A L
AN
E S T H E S I A A N D
34. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1): 30–36. 35. Dirks J, Fredensborg BB, Christensen D, et al. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology. 2002;97(3):560–564. 36. Fassoulaki A, Triga A, Melemeni A, et al. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg. 2005;101:1427–1432. 37. Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-Daspartate receptor for chronic pain management. J Pain Symptom Manage. 2000;20(5):358–373. 38. McCartney C, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg. 2004:1385–1400. 39. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5): 588–593. 40. Habib AS, Gan TJ. Use of neostigmine in the management of acute postoperative pain and labour pain. CNS Drugs. 2006;20(10): 821–839. 41. Abdulatif M, El-Sanabary M. Caudal neostigmine, bupivacaine, and their combination for postoperative pain management after hypospadias surgery in children. Anesth Analg. 2002;95(5):1215–1218. 42. Levaux CH, Bonhomme V, Dewandre PY, et al. Effect of intraoperative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia. 2003;58(2):131–135. 43. Mentes O, Harlak A, Yigit T, et al. Effect of intraoperative magnesium sulphate infusion on pain relief after laparoscopic cholecystectomy. Acta Anaesthesiol Scand. 2008;52(10): 1353–1359. 44. Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56: 514–517. 45. Houmes RJ, Voets MA, Verkaaik A, et al. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg. 1992;74(4):510–514.
PA
I N
MA
N A G E M E N T
18 (2014) 92–99
99
46. Scott LJ, Perry CM. Tramadol. Drugs. 2000;60(1):139–176. 47. Raffa RB, Buschmann H, Christoph T, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 2012;13(10):1437–1449. 48. Stenseth K, Sellevold O, Breivik H. Epidural morphine for postoperative pain: experience with 1085 patients. Acta Anaesthesiol Scand. 1985;29(1):148–156. 49. Kokki H, Kokki M, Sjövall S. Oxycodone for the treatment of postoperative pain. Expert Opin Pharmacother. 2012;13(7): 1045–1058. 50. Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97(2):534–540. 51. Gaskell H, Derry S, Moore RA, et al. Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009;3: CD002763. http://dx.doi.org/10.1002/14651858.cd002763.pub2. 52. Lim B, Thong SY, Zhu HB, et al. Pre-medication with controlled-release oxycodone in the management of postoperative pain after ambulatory laparoscopic gynaecological surgery. OA Case Rep. 2013;2(4):40. 53. Information for Health Care Professionals. Cannabis (marihuana, marijuana) and the cannabinoids Health Canada, 2013. Available at: http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/ infoprof-eng.phptphp. 54. Holdcroft A, Maze M, Dore C, et al. A multicenter doseescalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104(5):1040–1046. 55. Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol. 1981;21(S1):320S–326S. 56. Buggy DJ, Toogood L, Maric S, et al. Lack of analgesic efficacy of oral δ-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1):169–172. 57. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anesth. 2006;53(8):769–775. 58. Vargas-Schaffer G, Cogan J. Patient therapeutic education: placing the patient at the centre of the WHO analgesic ladder. Can Fam Physician. 2014;60(3):234–241.