Current Oncology Reports

, 18:71 | Cite as

Opioids and Chronic Pain: Where Is the Balance?

Palliative Medicine (A Jatoi, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Palliative Medicine


Chronic opioid therapy (defined as greater than 3 months on opioids) is a common practice for those with non-cancer pain, cancer survivors with treatment-related pain, and individuals with cancer undergoing disease-modifying therapy with a survival that can be for a year or more. Recent studies have found unique long-term toxicities with opioids which reduce the utility of opioid therapy in chronic pain. The risk of addiction, depression, central hypogonadism, sleep-disordered breathing, impaired wound healing, infections, cognitive impairment, falls, non-vertebral fractures, and mortality are increased in populations on long-term opioids. Factors associated with these risks are related to dose, duration of opioid therapy, type of opioid, and formula (long-acting, short-acting). This state-of-the-art review discusses the risks and benefits of chronic opioid therapy and strategies to increase utility and diminish risks to opioid therapy.


Opioid Pain Intensity Depression Sleep-disordered breathing Infection Cognitive Fall fracture Wound healing 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Mularski RA, White-Chu F, Overbay D, Miller L, Asch SM, Ganzini L. Measuring pain as the 5th vital sign does not improve quality of pain management. J Gen Intern Med. 2006;21(6):607–12.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Toblin RL, Mack KA, Perveen G, Paulozzi LJ. A population-based survey of chronic pain and its treatment with prescription drugs. Pain. 2011;152(6):1249–55.CrossRefPubMedGoogle Scholar
  3. 3.
    ••Lee TH. Zero pain is not the goal. Jama. 2016;315(15):1575–7. This is an important essay which clinicians should read to get a perspective on opioid therapy and patients.CrossRefPubMedGoogle Scholar
  4. 4.
    Kolodny A, Courtwright DT, Hwang CS, Kreiner P, Eadie JL, Clark TW, et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu Rev Public Health. 2015;36:559–74.CrossRefPubMedGoogle Scholar
  5. 5.
    ••Ballantyne JC, Sullivan MD. Intensity of Chronic Pain. N Engl J Med. 2016;374(14):1395. This essay puts the use of pain intensity for chronic pain outcomes in a new light.CrossRefPubMedGoogle Scholar
  6. 6.
    •Ballantyne JC, Kalso E, Stannard C. WHO analgesic ladder: a good concept gone astray. BMJ. 2016;352:i20. The WHO ananlgesic ladder was intended for advanced cancer pain is a dangerous strategy in managing chronic pain.CrossRefPubMedGoogle Scholar
  7. 7.
    ••Chen L, Vo T, Seefeld L, Malarick C, Houghton M, Ahmed S, et al. Lack of correlation between opioid dose adjustment and pain score change in a group of chronic pain patients. J Pain. 2013;14(4):384–92. Patients with chronic pain on chronic opioid therapy do not improve with dose escalation or worsen with dose reduction.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Naliboff BD, Wu SM, Schieffer B, Bolus R, Pham Q, Baria A, et al. A randomized trial of 2 prescription strategies for opioid treatment of chronic nonmalignant pain. J Pain. 2011;12(2):288–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. Jama. 2016;315(15):1624–45.CrossRefPubMedGoogle Scholar
  10. 10.
    Ballantyne JC. Avoiding opioid analgesics for treatment of chronic low back pain. Jama. 2016;315(22):2459–60.CrossRefPubMedGoogle Scholar
  11. 11.
    Webster BS, Verma SK, Gatchel RJ. Relationship between early opioid prescribing for acute occupational low back pain and disability duration, medical costs, subsequent surgery and late opioid use. Spine. 2007;32(19):2127–32.CrossRefPubMedGoogle Scholar
  12. 12.
    Cassell EJ. The importance of understanding suffering for clinical ethics. J Clin Ethics. 1991;2(2):81–2.PubMedGoogle Scholar
  13. 13.
    Cassell EJ. The relief of suffering. Arch Intern Med. 1983;143(3):522–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Gaither JR, Goulet JL, Becker WC, Crystal S, Edelman EJ, Gordon K, et al. The association between receipt of guideline-concordant long-term opioid therapy and all-cause mortality. J Gen Intern Med. 2016;31(5):492–501.CrossRefPubMedGoogle Scholar
  15. 15.
    Aronoff GM. What do we know about the pathophysiology of chronic pain? Implications for treatment considerations. Med Clin N Am. 2016;100(1):31–42.CrossRefPubMedGoogle Scholar
  16. 16.
    Yarnitsky D, Dahan A. Endogenous pain modulation: from humans to animals and back. Anesthesiology. 2015;122(4):734–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Heinricher MM, Maire JJ, Lee D, Nalwalk JW, Hough LB. Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. J Neurophysiol. 2010;104(6):3222–30.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: specificity, recruitment and plasticity. Brain Res Rev. 2009;60(1):214–25.CrossRefPubMedGoogle Scholar
  19. 19.
    Mase H, Sakai A, Sakamoto A, Suzuki H. A subset of mu-opioid receptor-expressing cells in the rostral ventromedial medulla contribute to thermal hyperalgesia in experimental neuropathic pain. Neurosci Res. 2011;70(1):35–43.CrossRefPubMedGoogle Scholar
  20. 20.
    Vanderah TW, Suenaga NM, Ossipov MH, Malan Jr TP, Lai J, Porreca F. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci Off J Soc Neurosci. 2001;21(1):279–86.Google Scholar
  21. 21.
    Kincaid W, Neubert MJ, Xu M, Kim CJ, Heinricher MM. Role for medullary pain facilitating neurons in secondary thermal hyperalgesia. J Neurophysiol. 2006;95(1):33–41.CrossRefPubMedGoogle Scholar
  22. 22.
    Schepers RJ, Mahoney JL, Shippenberg TS. Inflammation-induced changes in rostral ventromedial medulla mu and kappa opioid receptor mediated antinociception. Pain. 2008;136(3):320–30.CrossRefPubMedGoogle Scholar
  23. 23.
    Upadhyay J, Maleki N, Potter J, Elman I, Rudrauf D, Knudsen J, et al. Alterations in brain structure and functional connectivity in prescription opioid-dependent patients. Brain. 2010;133(Pt 7):2098–114.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Upadhyay J, Anderson J, Baumgartner R, Coimbra A, Schwarz AJ, Pendse G, et al. Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine. NeuroImage. 2012;59(4):3762–73.CrossRefPubMedGoogle Scholar
  25. 25.
    Aoki Y, Mizoguchi H, Watanabe C, Takeda K, Sakurada T, Sakurada S. Potential involvement of mu-opioid receptor dysregulation on the reduced antinociception of morphine in the inflammatory pain state in mice. J Pharmacol Sci. 2014;124(2):258–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Mantyh PW. Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care. 2014;8(2):83–90.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jimenez-Andrade JM, Bloom AP, Stake JI, Mantyh WG, Taylor RN, Freeman KT, et al. Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. J Neurosci Off J Soc Neurosci. 2010;30(44):14649–56.CrossRefGoogle Scholar
  28. 28.
    Lechner B, Chow S, Chow R, Zhang L, Tsao M, Danjoux C, et al. The incidence of neuropathic pain in bone metastases patients referred for palliative radiotherapy. Radiother Oncol. 2016;118(3):557–61.CrossRefPubMedGoogle Scholar
  29. 29.
    Karshikoff B, Jensen KB, Kosek E, Kalpouzos G, Soop A, Ingvar M, et al. Why sickness hurts: a central mechanism for pain induced by peripheral inflammation. Brain Behav Immun. 2016.Google Scholar
  30. 30.
    Hannestad J, Gallezot JD, Schafbauer T, Lim K, Kloczynski T, Morris ED, et al. Endotoxin-induced systemic inflammation activates microglia: [(1)(1)C]PBR28 positron emission tomography in nonhuman primates. NeuroImage. 2012;63(1):232–9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ren K. Emerging role of astroglia in pain hypersensitivity. Jpn Dent Sci Rev. 2010;46(1):86.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16(11):1267–76.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Caraceni A, Zecca E, Martini C, Pigni A, Bracchi P. Gabapentin for breakthrough pain due to bone metastases. Palliat Med. 2008;22(4):392–3.CrossRefPubMedGoogle Scholar
  34. 34.
    Caraceni A, Zecca E, Bonezzi C, Arcuri E, Yaya Tur R, Maltoni M, et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(14):2909–17.CrossRefGoogle Scholar
  35. 35.
    Lu Y, Westlund KN. Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats. J Pharmacol Exp Ther. 1999;290(1):214–9.PubMedGoogle Scholar
  36. 36.
    Yang JL, Xu B, Li SS, Zhang WS, Xu H, Deng XM, et al. Gabapentin reduces CX3CL1 signaling and blocks spinal microglial activation in monoarthritic rats. Mol Brain. 2012;5:18.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Martikainen IK, Pecina M, Love TM, Nuechterlein EB, Cummiford CM, Green CR, et al. Alterations in endogenous opioid functional measures in chronic back pain. J Neurosci Off J Soc Neurosci. 2013;33(37):14729–37.CrossRefGoogle Scholar
  38. 38.
    Stohler CS, Kowalski CJ. Spatial and temporal summation of sensory and affective dimensions of deep somatic pain. Pain. 1999;79(2–3):165–73.CrossRefPubMedGoogle Scholar
  39. 39.
    Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001;293(5528):311–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Lopez-de-Uralde-Villanueva I, Beltran-Alacreu H, Fernandez-Carnero J, Kindelan-Calvo P, La Touche R. Widespread pressure pain hyperalgesia in chronic nonspecific neck pain with neuropathic features: a descriptive cross-sectional study. Pain Physician. 2016;19(2):77–88.PubMedGoogle Scholar
  41. 41.
    Lopez-de-Uralde-Villanueva I, Beltran-Alacreu H, Fernandez-Carnero J, Gil-Martinez A, La Touche R. Differences in neural mechanosensitivity between patients with chronic nonspecific neck pain with and without neuropathic features. A descriptive cross-sectional study. Pain Med. 2016;17(1):136–48.PubMedGoogle Scholar
  42. 42.
    Bruehl S, Burns JW, Passik SD, Gupta R, Buvanendran A, Chont M, et al. The contribution of differential opioid responsiveness to identification of opioid risk in chronic pain patients. J Pain. 2015;16(7):666–75.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci. 2012;15(8):1117–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73(4):638–52.CrossRefGoogle Scholar
  45. 45.
    Backonja M, Woolf CJ. Future directions in neuropathic pain therapy: closing the translational loop. Oncologist. 2010;15 Suppl 2:24–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Edwards RR, Dworkin RH, Turk DC, Angst MS, Dionne R, Freeman R, et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain. 2016.Google Scholar
  47. 47.
    Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372–80.CrossRefPubMedGoogle Scholar
  48. 48.
    Koltzenburg M, Pokorny R, Gasser UE, Richarz U. Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine. Pain. 2006;126(1–3):165–74.CrossRefPubMedGoogle Scholar
  49. 49.
    Rothwell PM. Can overall results of clinical trials be applied to all patients? Lancet. 1995;345(8965):1616–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Kringel D, Ultsch A, Zimmermann M, Jansen JP, Ilias W, Freynhagen R, et al. Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses. The pharmacogenomics journal. 2016.Google Scholar
  51. 51.
    Zhang Y, Ahmed S, Vo T, St Hilaire K, Houghton M, Cohen AS, et al. Increased pain sensitivity in chronic pain subjects on opioid therapy: a cross-sectional study using quantitative sensory testing. Pain Med. 2015;16(5):911–22.CrossRefPubMedGoogle Scholar
  52. 52.
    Kirkpatrick DR, McEntire DM, Hambsch ZJ, Kerfeld MJ, Smith TA, Reisbig MD, et al. Therapeutic basis of clinical pain modulation. Clin Transl Sci. 2015;8(6):848–56.CrossRefPubMedGoogle Scholar
  53. 53.
    Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth. 2014;112(6):991–1004.CrossRefPubMedGoogle Scholar
  54. 54.
    Chen L, Malarick C, Seefeld L, Wang S, Houghton M, Mao J. Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain. 2009;143(1–2):65–70.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wang H, Akbar M, Weinsheimer N, Gantz S, Schiltenwolf M. Longitudinal observation of changes in pain sensitivity during opioid tapering in patients with chronic low-back pain. Pain Med. 2011;12(12):1720–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Carullo V, Fitz-James I, Delphin E. Opioid-induced hyperalgesia: a diagnostic dilemma. J Pain Palliat Care Pharmacother. 2015;29(4):378–84.CrossRefPubMedGoogle Scholar
  57. 57.
    Mao J. Clinical diagnosis of opioid-induced hyperalgesia. Reg Anesth Pain Med. 2015;40(6):663–4.CrossRefPubMedGoogle Scholar
  58. 58.
    Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14(2):145–61.PubMedGoogle Scholar
  59. 59.
    Grace PM, Ramos KM, Rodgers KM, Wang X, Hutchinson MR, Lewis MT, et al. Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae. Neuroscience. 2014;280:299–317.CrossRefPubMedGoogle Scholar
  60. 60.
    Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR. Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. TheScientificWorldJOURNAL. 2007;7:98–111.CrossRefPubMedGoogle Scholar
  61. 61.
    Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N, et al. Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun. 2008;22(8):1178–89.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hutchinson MR, Shavit Y, Grace PM, Rice KC, Maier SF, Watkins LR. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol Rev. 2011;63(3):772–810.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Lee C, Lee HW, Kim JN. Effect of oral pregabalin on opioid-induced hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery. Korean J Anesthesiol. 2013;64(1):19–24.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Juni A, Klein G, Pintar JE, Kest B. Nociception increases during opioid infusion in opioid receptor triple knock-out mice. Neuroscience. 2007;147(2):439–44.CrossRefPubMedGoogle Scholar
  65. 65.
    Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun. 2010;24(1):83–95.CrossRefPubMedGoogle Scholar
  66. 66.
    Blondell RD, Ashrafioun L, Dambra CM, Foschio EM, Zielinski AL, Salcedo DM. A clinical trial comparing tapering doses of buprenorphine with steady doses for chronic pain and co-existent opioid addiction. J Addict Med. 2010;4(3):140–6.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Vorobeychik Y, Chen L, Bush MC, Mao J. Improved opioid analgesic effect following opioid dose reduction. Pain Med. 2008;9(6):724–7.CrossRefPubMedGoogle Scholar
  68. 68.
    Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician. 2010;13(5):401–35.PubMedGoogle Scholar
  69. 69.
    Manchikanti L, Vallejo R, Manchikanti KN, Benyamin RM, Datta S, Christo PJ. Effectiveness of long-term opioid therapy for chronic non-cancer pain. Pain Physician. 2011;14(2):E133–56.PubMedGoogle Scholar
  70. 70.
    Manchikanti L, Singh V, Cash KA, Pampati V, Damron KS, Boswell MV. A randomized, controlled, double-blind trial of fluoroscopic caudal epidural injections in the treatment of lumbar disc herniation and radiculitis. Spine. 2011;36(23):1897–905.CrossRefPubMedGoogle Scholar
  71. 71.
    Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, et al. Constitutive mu-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013;341(6152):1394–9.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU. Endogenous opioid-masked latent pain sensitization: studies from mouse to human. PLoS One. 2015;10(8), e0134441.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Kenakin T. Inverse, protean, and ligand-selective agonism: matters of receptor conformation. FASEB J. 2001;15(3):598–611.CrossRefPubMedGoogle Scholar
  74. 74.
    Connor M, Traynor J. Constitutively active mu-opioid receptors. Methods Enzymol. 2010;484:445–69.CrossRefPubMedGoogle Scholar
  75. 75.
    Walwyn W, Evans CJ, Hales TG. Beta-arrestin2 and c-Src regulate the constitutive activity and recycling of mu opioid receptors in dorsal root ganglion neurons. J Neurosci Off J Soc Neurosci. 2007;27(19):5092–104.CrossRefGoogle Scholar
  76. 76.
    Ellis A, Grace PM, Wieseler J, Favret J, Springer K, Skarda B, et al. Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury. Brain Behav Immun. 2016.Google Scholar
  77. 77.
    Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci U S A. 2016;113(24):E3441–50.CrossRefPubMedGoogle Scholar
  78. 78.
    Wasan AD, Michna E, Edwards RR, Katz JN, Nedeljkovic SS, Dolman AJ, et al. Psychiatric comorbidity is associated prospectively with diminished opioid analgesia and increased opioid misuse in patients with chronic low back pain. Anesthesiology. 2015;123(4):861–72.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Jamison RN, Edwards RR, Liu X, Ross EL, Michna E, Warnick M, et al. Relationship of negative affect and outcome of an opioid therapy trial among low back pain patients. Pain Pract. 2013;13(3):173–81.CrossRefPubMedGoogle Scholar
  80. 80.
    Edwards RR, Wasan AD, Michna E, Greenbaum S, Ross E, Jamison RN. Elevated pain sensitivity in chronic pain patients at risk for opioid misuse. J Pain. 2011;12(9):953–63.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Edwards RR, Dolman AJ, Michna E, Katz JN, Nedeljkovic SS, Janfaza D, et al. Changes in pain sensitivity and pain modulation during oral opioid treatment: the impact of negative affect. Pain Med. 2016.Google Scholar
  82. 82.
    •Scherrer JF, Salas J, Sullivan MD, Schneider FD, Bucholz KK, Burroughs T, et al. The influence of prescription opioid use duration and dose on development of treatment resistant depression. Prev Med. 2016. This is a new findings associated with opioid therapy.Google Scholar
  83. 83.
    Scherrer JF, Salas J, Bucholz KK, Schneider FD, Burroughs T, Copeland LA, et al. New depression diagnosis following prescription of codeine, hydrocodone or oxycodone. Pharmacoepidemiol Drug Saf. 2016;25(5):560–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Scherrer JF, Salas J, Copeland LA, Stock EM, Schneider FD, Sullivan M, et al. Increased risk of depression recurrence after initiation of prescription opioids in noncancer pain patients. J Pain. 2016;17(4):473–82.CrossRefPubMedGoogle Scholar
  85. 85.
    Scherrer JF, Salas J, Lustman PJ, Burge S, Schneider FD. Residency Research Network of Texas I. Change in opioid dose and change in depression in a longitudinal primary care patient cohort. Pain. 2015;156(2):348–55.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Scherrer JF, Svrakic DM, Freedland KE, Chrusciel T, Balasubramanian S, Bucholz KK, et al. Prescription opioid analgesics increase the risk of depression. J Gen Intern Med. 2014;29(3):491–9.CrossRefPubMedGoogle Scholar
  87. 87.
    Chiou CS, Chen CC, Tsai TC, Huang CC, Chou D, Hsu KS. Alleviating bone cancer-induced mechanical hypersensitivity by inhibiting neuronal activity in the anterior cingulate cortex. Anesthesiology. 2016.Google Scholar
  88. 88.
    Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry. 2015;77(3):236–45.CrossRefPubMedGoogle Scholar
  89. 89.
    Yalcin I, Barrot M. The anxiodepressive comorbidity in chronic pain. Curr Opin Anaesthesiol. 2014;27(5):520–7.CrossRefPubMedGoogle Scholar
  90. 90.
    Yalcin I, Barthas F, Barrot M. Emotional consequences of neuropathic pain: insight from preclinical studies. Neurosci Biobehav Rev. 2014;47:154–64.CrossRefPubMedGoogle Scholar
  91. 91.
    Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations. Anesth Analg. 2015;120(6):1273–85.CrossRefPubMedGoogle Scholar
  92. 92.
    Walker JM, Farney RJ, Rhondeau SM, Boyle KM, Valentine K, Cloward TV, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med. 2007;3(5):455–61.PubMedPubMedCentralGoogle Scholar
  93. 93.
    ••Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleep-disordered breathing and chronic opioid therapy. Pain Med. 2008;9(4):425–32. Most opioid deaths occur at night and it may be related to the high risk of central sleep apnea that occurs with opioids.CrossRefPubMedGoogle Scholar
  94. 94.
    Mogri M, Desai H, Webster L, Grant BJ, Mador MJ. Hypoxemia in patients on chronic opiate therapy with and without sleep apnea. Sleep Breath. 2009;13(1):49–57.CrossRefPubMedGoogle Scholar
  95. 95.
    Sharkey KM, Kurth ME, Anderson BJ, Corso RP, Millman RP, Stein MD. Obstructive sleep apnea is more common than central sleep apnea in methadone maintenance patients with subjective sleep complaints. Drug Alcohol Depend. 2010;108(1–2):77–83.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005;128(3):1348–56.CrossRefPubMedGoogle Scholar
  97. 97.
    Emery MJ, Groves CC, Kruse TN, Shi C, Terman GW. Ventilation and the response to hypercapnia after morphine in opioid-naive and opioid-tolerant rats. Anesthesiology. 2016;124(4):945–57.CrossRefPubMedGoogle Scholar
  98. 98.
    Feldman JL, Del Negro CA. Looking for inspiration: new perspectives on respiratory rhythm. Nat Rev Neurosci. 2006;7(3):232–42.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Lalley PM. Opioidergic and dopaminergic modulation of respiration. Respir Physiol Neurobiol. 2008;164(1–2):160–7.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Pattinson KT, Mitsis GD, Harvey AK, Jbabdi S, Dirckx S, Mayhew SD, et al. Determination of the human brainstem respiratory control network and its cortical connections in vivo using functional and structural imaging. NeuroImage. 2009;44(2):295–305.CrossRefPubMedGoogle Scholar
  101. 101.
    Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747–58.CrossRefPubMedGoogle Scholar
  102. 102.
    Reddy R, Adamo D, Kufel T, Porhomayon J, El-Solh AA. Treatment of opioid-related central sleep apnea with positive airway pressure: a systematic review. J Opioid Manag. 2014;10(1):57–62.CrossRefPubMedGoogle Scholar
  103. 103.
    Farney RJ, Walker JM, Boyle KM, Cloward TV, Shilling KC. Adaptive servoventilation (ASV) in patients with sleep disordered breathing associated with chronic opioid medications for non-malignant pain. J Clin Sleep Med. 2008;4(4):311–9.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Javaheri S, Malik A, Smith J, Chung E. Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids. J Clin Sleep Med. 2008;4(4):305–10.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Wang D, Lintzeris N, Leung S, Haber PS, Yee BJ, Grunstein RR. Reversal of central sleep apnoea with change from methadone to buprenorphine-naloxone: a case report. Eur Respir J. 2015;46(4):1202–5.CrossRefPubMedGoogle Scholar
  106. 106.
    Boykoff N, Moieni M, Subramanian SK. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. J Cancer Surviv. 2009;3(4):223–32.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Baldacchino A, Balfour DJ, Passetti F, Humphris G, Matthews K. Neuropsychological consequences of chronic opioid use: a quantitative review and meta-analysis. Neurosci Biobehav Rev. 2012;36(9):2056–68.CrossRefPubMedGoogle Scholar
  108. 108.
    Sjogren P, Olsen AK, Thomsen AB, Dalberg J. Neuropsychological performance in cancer patients: the role of oral opioids, pain and performance status. Pain. 2000;86(3):237–45.CrossRefPubMedGoogle Scholar
  109. 109.
    Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2(3):137–46.PubMedGoogle Scholar
  110. 110.
    Tassain V, Attal N, Fletcher D, Brasseur L, Degieux P, Chauvin M, et al. Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain. Pain. 2003;104(1–2):389–400.CrossRefPubMedGoogle Scholar
  111. 111.
    Kurita GP, Pimenta CA, Nobre MR. Opioids and cognition in patients with chronic pain: a systematic review. Rev Assoc Med Bras. 2008;54(6):529–36.CrossRefPubMedGoogle Scholar
  112. 112.
    Kurita GP, Lundorff L, Pimenta CA, Sjogren P. The cognitive effects of opioids in cancer: a systematic review. Supportive Care Cancer. 2009;17(1):11–21.CrossRefGoogle Scholar
  113. 113.
    Sjogren P, Banning A. Pain, sedation and reaction time during long-term treatment of cancer patients with oral and epidural opioids. Pain. 1989;39(1):5–11.CrossRefPubMedGoogle Scholar
  114. 114.
    Hojsted J, Kurita GP, Kendall S, Lundorff L, de Mattos Pimenta CA, Sjogren P. Non-analgesic effects of opioids: the cognitive effects of opioids in chronic pain of malignant and non-malignant origin. An update. Curr Pharm Des. 2012;18(37):6116–22.CrossRefPubMedGoogle Scholar
  115. 115.
    Kurita GP, de Mattos Pimenta CA, Braga PE, Frich L, Jorgensen MM, Nielsen PR, et al. Cognitive function in patients with chronic pain treated with opioids: characteristics and associated factors. Acta Anaesthesiol Scand. 2012;56(10):1257–66.CrossRefPubMedGoogle Scholar
  116. 116.
    Schiltenwolf M, Akbar M, Hug A, Pfuller U, Gantz S, Neubauer E, et al. Evidence of specific cognitive deficits in patients with chronic low back pain under long-term substitution treatment of opioids. Pain Physician. 2014;17(1):9–20.PubMedGoogle Scholar
  117. 117.
    Kurita GP, Sjogren P, Ekholm O, Kaasa S, Loge JH, Poviloniene I, et al. Prevalence and predictors of cognitive dysfunction in opioid-treated patients with cancer: a multinational study. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1297–303.CrossRefGoogle Scholar
  118. 118.
    Kurita GP, Ekholm O, Kaasa S, Klepstad P, Skorpen F, Sjogren P. Genetic variation and cognitive dysfunction in opioid-treated patients with cancer. Brain Behav. 2016;6(7), e00471.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Khodayari-Rostamabad A, Olesen SS, Graversen C, Malver LP, Kurita GP, Sjogren P, et al. Disruption of cortical connectivity during remifentanil administration is associated with cognitive impairment but not with analgesia. Anesthesiology. 2015;122(1):140–9.CrossRefPubMedGoogle Scholar
  120. 120.
    Bruera E, El Osta B, Valero V, Driver LC, Pei BL, Shen L, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(23):3475–81.CrossRefGoogle Scholar
  121. 121.
    Bruera E, Strasser F, Shen L, Palmer JL, Willey J, Driver LC, et al. The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: a pilot study. J Pain Symptom Manag. 2003;26(5):1049–54.CrossRefGoogle Scholar
  122. 122.
    Khojainova N, Santiago-Palma J, Kornick C, Breitbart W, Gonzales GR. Olanzapine in the management of cancer pain. J Pain Symptom Manag. 2002;23(4):346–50.CrossRefGoogle Scholar
  123. 123.
    Kamboj SK, Tookman A, Jones L, Curran HV. The effects of immediate-release morphine on cognitive functioning in patients receiving chronic opioid therapy in palliative care. Pain. 2005;117(3):388–95.CrossRefPubMedGoogle Scholar
  124. 124.
    Gudin JA, Laitman A, Nalamachu S. Opioid related endocrinopathy. Pain Med. 2015;16 Suppl 1:S9–15.CrossRefPubMedGoogle Scholar
  125. 125.
    Aloisi AM, Aurilio C, Bachiocco V, Biasi G, Fiorenzani P, Pace MC, et al. Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009;34 Suppl 1:S162–8.CrossRefPubMedGoogle Scholar
  126. 126.
    Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100(4):851–8.CrossRefPubMedGoogle Scholar
  127. 127.
    Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008;9(1):28–36.CrossRefPubMedGoogle Scholar
  128. 128.
    Daniell HW. DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production. J Pain. 2006;7(12):901–7.CrossRefPubMedGoogle Scholar
  129. 129.
    Rubinstein A, Carpenter DM. Elucidating risk factors for androgen deficiency associated with daily opioid use. Am J Med. 2014;127(12):1195–201.CrossRefPubMedGoogle Scholar
  130. 130.
    Elliott JA, Horton E, Fibuch EE. The endocrine effects of long-term oral opioid therapy: a case report and review of the literature. J Opioid Manag. 2011;7(2):145–54.PubMedGoogle Scholar
  131. 131.
    Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009;25(2):170–5.CrossRefPubMedGoogle Scholar
  132. 132.
    Kalyani RR, Gavini S, Dobs AS. Male hypogonadism in systemic disease. Endocrinol Metab Clin N Am. 2007;36(2):333–48.CrossRefGoogle Scholar
  133. 133.
    Aloisi AM, Ceccarelli I, Fiorenzani P, Maddalena M, Rossi A, Tomei V, et al. Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats. Mol Pain. 2010;6:69.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ. American Association of Clinical E. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update. Endocr Pract. 2002;8(6):440–56.PubMedGoogle Scholar
  135. 135.
    Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl. 2009;30(1):1–9.CrossRefPubMedGoogle Scholar
  136. 136.
    Yeap BB, Grossmann M, McLachlan RI, Handelsman DJ, Wittert GA, Conway AJ, et al. Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust. 2016;205(4):173–8.CrossRefPubMedGoogle Scholar
  137. 137.
    Rajagopal A, Bruera ED. Improvement in sexual function after reduction of chronic high-dose opioid medication in a cancer survivor. Pain Med. 2003;4(4):379–83.CrossRefPubMedGoogle Scholar
  138. 138.
    Aloisi AM, Ceccarelli I, Carlucci M, Suman A, Sindaco G, Mameli S, et al. Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients. Reprod Biol Endocrinol. 2011;9:26.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Basaria S, Travison TG, Alford D, Knapp PE, Teeter K, Cahalan C, et al. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain. 2015;156(2):280–8.CrossRefPubMedGoogle Scholar
  140. 140.
    Khera M, Bhattacharya RK, Blick G, Kushner H, Nguyen D, Miner MM. The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim Registry in the US (TRiUS). Aging Male. 2012;15(1):14–21.CrossRefPubMedGoogle Scholar
  141. 141.
    Huang G, Travison T, Maggio M, Edwards RR, Basaria S. Effects of testosterone replacement on metabolic and inflammatory markers in men with opioid-induced androgen deficiency. Clin Endocrinol. 2016;85(2):232–8.CrossRefGoogle Scholar
  142. 142.
    Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of myocardial infarction amongst adults. J Intern Med. 2013;273(5):511–26.CrossRefPubMedGoogle Scholar
  143. 143.
    Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Physician. 2012;15(3 Suppl):ES145–56.PubMedGoogle Scholar
  144. 144.
    Aparasu RR, Chatterjee S, Chen H. Risk of hospitalization and use of first- versus second-generation antipsychotics among nursing home residents. Psychiatr Serv. 2014;65(6):781–8.CrossRefPubMedGoogle Scholar
  145. 145.
    Soderberg KC, Laflamme L, Moller J. Newly initiated opioid treatment and the risk of fall-related injuries. A nationwide, register-based, case-crossover study in Sweden. CNS Drugs. 2013;27(2):155–61.CrossRefPubMedGoogle Scholar
  146. 146.
    Acurcio FA, Moura CS, Bernatsky S, Bessette L, Rahme E. Opioid use and risk of nonvertebral fractures in adults with rheumatoid arthritis: a nested case–control study using administrative databases. Arthritis Rheum. 2016;68(1):83–91.CrossRefGoogle Scholar
  147. 147.
    Hirst A, Knight C, Hirst M, Dunlop W, Akehurst R. Tramadol and the risk of fracture in an elderly female population: a cost utility assessment with comparison to transdermal buprenorphine. Eur J Health Econ. 2016;17(2):217–27.CrossRefPubMedGoogle Scholar
  148. 148.
    Saunders KW, Dunn KM, Merrill JO, Sullivan M, Weisner C, Braden JB, et al. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. J Gen Intern Med. 2010;25(4):310–5.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of fracture in adults: a nested case–control study using the general practice research database. Am J Epidemiol. 2013;178(4):559–69.CrossRefPubMedGoogle Scholar
  150. 150.
    Coluzzi F, Pergolizzi J, Raffa RB, Mattia C. The unsolved case of “bone-impairing analgesics”: the endocrine effects of opioids on bone metabolism. Ther Clin Risk Manag. 2015;11:515–23.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Shanmugam VK, Fernandez SJ, Evans KK, McNish S, Banerjee AN, Couch KS, et al. Postoperative wound dehiscence: predictors and associations. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair. Society. 2015;23(2):184–90.Google Scholar
  152. 152.
    Kuchler S, Wolf NB, Heilmann S, Weindl G, Helfmann J, Yahya MM, et al. 3D-wound healing model: influence of morphine and solid lipid nanoparticles. J Biotechnol. 2010;148(1):24–30.CrossRefPubMedGoogle Scholar
  153. 153.
    Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S. Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. Am J Pathol. 2010;176(2):786–99.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Martin JL, Charboneau R, Barke RA, Roy S. Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing. Cell Immunol. 2010;265(2):139–45.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Immonen JA, Zagon IS, Lewis GS, McLaughlin PJ. Topical treatment with the opioid antagonist naltrexone accelerates the remodeling phase of full-thickness wound healing in type 1 diabetic rats. Exp Biol Med. 2013;238(10):1127–35.CrossRefGoogle Scholar
  156. 156.
    McLaughlin PJ, Immonen JA, Zagon IS. Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis. Exp Biol Med. 2013;238(7):733–43.CrossRefGoogle Scholar
  157. 157.
    Chrastil J, Sampson C, Jones KB, Higgins TF. Evaluating the affect and reversibility of opioid-induced androgen deficiency in an orthopaedic animal fracture model. Clin Orthop Relat Res. 2014;472(6):1964–71.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Matziolis G, Rau HM, Klever P, Erli HJ, Paar O. Modification of human osteoblasts by various analgesics. Unfallchirurg. 2002;105(6):527–31.CrossRefPubMedGoogle Scholar
  159. 159.
    Ozkan D, Seker D, Ergil J, Yalcindag A, Han U, Ginis Z, et al. The effects of tramadol infiltration on wound healing in rats. Acta Chir Belg. 2013;113(6):434–8.PubMedGoogle Scholar
  160. 160.
    Ronan MV, Herzig SJ. Hospitalizations related to opioid abuse/dependence and associated serious infections increased sharply, 2002–12. Health Aff. 2016;35(5):832–7.CrossRefGoogle Scholar
  161. 161.
    Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther. 2004;11(5):354–65.CrossRefPubMedGoogle Scholar
  162. 162.
    Tubaro E, Borelli G, Croce C, Cavallo G, Santiangeli C. Effect of morphine on resistance to infection. J Infect Dis. 1983;148(4):656–66.CrossRefPubMedGoogle Scholar
  163. 163.
    Wang J, Barke RA, Charboneau R, Roy S. Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol. 2005;174(1):426–34.CrossRefPubMedGoogle Scholar
  164. 164.
    Dublin S, Walker RL, Jackson ML, Nelson JC, Weiss NS, Von Korff M, et al. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case–control study. J Am Geriatr Soc. 2011;59(10):1899–907.CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Yeager MP, Colacchio TA, Yu CT, Hildebrandt L, Howell AL, Weiss J, et al. Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology. 1995;83(3):500–8.CrossRefPubMedGoogle Scholar
  166. 166.
    Hendrickson M, Shelby J, Sullivan JJ, Saffle JR. Naloxone inhibits the in vivo immunosuppressive effects of morphine and thermal injury in mice. J Burn Care Rehabil. 1989;10(6):494–8.CrossRefPubMedGoogle Scholar
  167. 167.
    Ballard KA, Pellegrino TC, Alonzo NC, Nugent AL, Bayer BM. Enhanced immune sensitivity to stress following chronic morphine exposure. J Neuroimmune Pharmacol. 2006;1(1):106–15.CrossRefPubMedGoogle Scholar
  168. 168.
    Bryant HU, Roudebush RE. Suppressive effects of morphine pellet implants on in vivo parameters of immune function. J Pharmacol Exp Ther. 1990;255(2):410–4.PubMedGoogle Scholar
  169. 169.
    Ninkovic J, Roy S. Role of the mu-opioid receptor in opioid modulation of immune function. Amino Acids. 2013;45(1):9–24.CrossRefPubMedGoogle Scholar
  170. 170.
    Banerjee S, Sindberg G, Wang F, Meng J, Sharma U, Zhang L, et al. Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol. 2016.Google Scholar
  171. 171.
    Meng J, Banerjee S, Li D, Sindberg GM, Wang F, Ma J, et al. Opioid exacerbation of gram-positive sepsis, induced by gut microbial modulation, is rescued by IL-17A neutralization. Sci Rep. 2015;5:10918.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Liu B, Liu X, Tang SJ. Interactions of opioids and HIV infection in the pathogenesis of chronic pain. Front Microbiol. 2016;7:103.PubMedPubMedCentralGoogle Scholar
  173. 173.
    El-Hage N, Rodriguez M, Dever SM, Masvekar RR, Gewirtz DA, Shacka JJ. HIV-1 and morphine regulation of autophagy in microglia: limited interactions in the context of HIV-1 infection and opioid abuse. J Virol. 2015;89(2):1024–35.CrossRefPubMedGoogle Scholar
  174. 174.
    Liang B, Jiang J, Pan P, Chen R, Zhuang D, Zhao F, et al. Morphine increases lamivudine- and nevirapine-induced human immunodeficiency virus-1 drug-resistant mutations in vitro. Microb Drug Resist. 2016.Google Scholar
  175. 175.
    Von Korff M, Merrill JO, Rutter CM, Sullivan M, Campbell CI, Weisner C. Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy. Pain. 2011;152(6):1256–62.CrossRefGoogle Scholar
  176. 176.
    Manchikanti L, Abdi S, Atluri S, Balog CC, Benyamin RM, Boswell MV, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician. 2012;15(3 Suppl):S67–116.PubMedGoogle Scholar
  177. 177.
    Manchikanti L, Abdi S, Atluri S, Balog CC, Benyamin RM, Boswell MV, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I--evidence assessment. Pain Physician. 2012;15(3 Suppl):S1–65.PubMedGoogle Scholar
  178. 178.
    Koyyalagunta D, Bruera E, Solanki DR, Nouri KH, Burton AW, Toro MP, et al. A systematic review of randomized trials on the effectiveness of opioids for cancer pain. Pain Physician. 2012;15(3 Suppl):ES39–58.PubMedGoogle Scholar
  179. 179.
    Drewes AM, Jensen RD, Nielsen LM, Droney J, Christrup LL, Arendt-Nielsen L, et al. Differences between opioids: pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol. 2013;75(1):60–78.CrossRefPubMedGoogle Scholar
  180. 180.
    Leider HL, Dhaliwal J, Davis EJ, Kulakodlu M, Buikema AR. Healthcare costs and nonadherence among chronic opioid users. Am J Manag Care. 2011;17(1):32–40.PubMedGoogle Scholar
  181. 181.
    Hakkinen M, Launiainen T, Vuori E, Ojanpera I. Comparison of fatal poisonings by prescription opioids. Forensic Sci Int. 2012;222(1–3):327–31.CrossRefPubMedGoogle Scholar
  182. 182.
    Coben JH, Davis SM, Furbee PM, Sikora RD, Tillotson RD, Bossarte RM. Hospitalizations for poisoning by prescription opioids, sedatives, and tranquilizers. Am J Prev Med. 2010;38(5):517–24.CrossRefPubMedGoogle Scholar
  183. 183.
    Centers for Disease C, Prevention. Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004–2008. MMWR Morb Mortal Wkly Rep. 2010;59(23):705–9.Google Scholar
  184. 184.
    Paulozzi LJ, Logan JE, Hall AJ, McKinstry E, Kaplan JA, Crosby AE. A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia. Addiction. 2009;104(9):1541–8.CrossRefPubMedGoogle Scholar
  185. 185.
    Jonsson T, Christrup LL, Hojsted J, Villesen HH, Albjerg TH, Ravn-Nielsen LV, et al. Symptoms and side effects in chronic non-cancer pain: patient report vs. systematic assessment. Acta Anaesthesiol Scand. 2011;55(1):69–74.CrossRefPubMedGoogle Scholar
  186. 186.
    Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;1, CD006605.Google Scholar
  187. 187.
    Devulder J, Richarz U, Nataraja SH. Impact of long-term use of opioids on quality of life in patients with chronic, non-malignant pain. Curr Med Res Opin. 2005;21(10):1555–68.CrossRefPubMedGoogle Scholar
  188. 188.
    Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on opioids in chronic non-cancer pain: an epidemiological study. Pain. 2006;125(1–2):172–9.CrossRefPubMedGoogle Scholar
  189. 189.
    Sjogren P, Gronbaek M, Peuckmann V, Ekholm O. A population-based cohort study on chronic pain: the role of opioids. Clin J Pain. 2010;26(9):763–9.CrossRefPubMedGoogle Scholar
  190. 190.
    Carmichael AN, Morgan L, Del Fabbro E. Identifying and assessing the risk of opioid abuse in patients with cancer: an integrative review. Subst Abuse Rehabil. 2016;7:71–9.PubMedPubMedCentralGoogle Scholar
  191. 191.
    Trang T, Al-Hasani R, Salvemini D, Salter MW, Gutstein H, Cahill CM. Pain and poppies: the good, the bad, and the ugly of opioid analgesics. J Neurosci Off J Soc Neurosci. 2015;35(41):13879–88.CrossRefGoogle Scholar
  192. 192.
    Bannister K. Opioid-induced hyperalgesia: where are we now? Curr Opin Support Palliat Care. 2015;9(2):116–21.CrossRefPubMedGoogle Scholar
  193. 193.
    Stoicea N, Russell D, Weidner G, Durda M, Joseph NC, Yu J, et al. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Front Pharmacol. 2015;6:104.CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Coluzzi F, Taylor Jr R, Pergolizzi Jr JV, Mattia C, Raffa RB. Good clinical practice guide for opioids in pain management: the three Ts - titration (trial), tweaking (tailoring), transition (tapering). Braz J Anesthesiol. 2016;66(3):310–7.CrossRefPubMedGoogle Scholar
  195. 195.
    Bihel F. Opioid adjuvant strategy: improving opioid effectiveness. Future Med Chem. 2016;8(3):339–54.CrossRefPubMedGoogle Scholar
  196. 196.
    Walsh TD, Saunders CM. Oral morphine for relief of chronic pain from cancer. N Engl J Med. 1981;305(23):1417–8.PubMedGoogle Scholar
  197. 197.
    Saunders C. Care of the dying-4. Control of pain in terminal cancer. Nurs Times. 1976;72(29):1133–5.PubMedGoogle Scholar
  198. 198.
    Saunders C. The treatment of intractable pain in terminal cancer. Proc R Soc Med. 1963;56:195–7.PubMedPubMedCentralGoogle Scholar
  199. 199.
    Saunders C. An individual approach to the relief of pain. In: People and cancer. London: The British Council; 1970. p. 34–8.Google Scholar
  200. 200.
    Saunders C. Current views in pain relief and terminology. In: Swerdlow M, editor. The therapy of pain. Lancaster, UK, 1981.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Palliative CareGeisinger Medical CenterDanvilleUSA

Personalised recommendations