Strength of evidence

[/vc_column_text][/vc_column][vc_column width=”1/12″ css=”.vc_custom_1509567896880{margin-right: 0px !important;margin-left: 0px !important;padding-right: 0px !important;padding-left: 0px !important;}” offset=”vc_col-xs-1 vc_hidden-xs”][vc_single_image image=”17803″ img_size=”full” el_class=”img-custom-width”][/vc_column][vc_column width=”2/3″ offset=”vc_col-sm-offset-0 vc_col-xs-12″][vc_column_text el_class=”custom-lis”]

[/vc_column_text][/vc_column][/vc_row][vc_row][vc_column width=”2/3″][dt_fancy_title title=”INTRODUCTION” title_align=”left” title_size=”h3″ title_color=”accent”][ultimate_spacer height=”10″][vc_column_text el_class=”h2-line”]Pain in cancer patients and survivors is very common and can be caused by the cancer itself invading organs, soft tissues (nerves and blood vessels) or bones, or the treatments for cancer, which include chemotherapy, radiotherapy, hormones and surgery. Multiple sites may be affected and multiple mechanisms are at play including inflammatory, neuropathic, ischemic and compression pain. Bone pain due to metastatic cancer is often particularly severe, unremitting and poorly controlled. Patients with bone pain need high doses of analgesic drugs, which are often associated with undesirable side-effects.1

Moderate to severe pain is experienced by 40% of individuals with early or intermediate stage cancer and 90% of individuals with advanced cancer. Up to 70% of all patients with cancer pain do not receive adequate pain relief, diminishing their quality of life in terms of both physical and psychological well-being.2[/vc_column_text][dt_fancy_title title=”ACUPUNCTURE FOR CANCER PAIN: THE CLINICAL EVIDENCE” title_align=”left” title_size=”h3″ title_color=”accent”][ultimate_spacer height=”10″][vc_column_text el_class=”h2-line”]A Comparative Literature Review in 2017 found a potentially positive effect of acupuncture in treating cancer pain.3 The review included two systematic reviews, the older of which was unable to draw firm conclusions due to small sample sizes and clinical differences in the patients being treated. The more recent review included 36 trials and over 2200 randomised patients. They found a moderate effect size of acupuncture on cancer-related pain, and concluded that “acupuncture is effective in relieving cancer-related pain, particularly malignancy-related and surgery-induced pain.”4

Although this review did not report on risks arising from treatment with acupuncture, elsewhere studies have indicated that acupuncture is a feasible and safe treatment56 and may successfully be used to treat cancer patients for symptom management due to the low risks associated with its use.7[/vc_column_text][/vc_column][vc_column width=”1/3″][dt_fancy_title title=”DOWNLOAD THE PDF” title_align=”left” title_size=”h3″ title_color=”accent”][ultimate_spacer height=”10″][vc_column_text]

Acupuncture for Cancer Pain PDF


[/vc_column_text][/vc_column][/vc_row][vc_row][vc_column width=”2/3″][dt_fancy_title title=”HOW ACUPUNCTURE TREATS CANCER PAIN: BIOLOGICAL MECHANISMS” title_align=”left” title_size=”h3″ title_color=”accent”][ultimate_spacer height=”10″][vc_column_text el_class=”h2-line”]Acupuncture’s mechanisms for treating cancer pain are thought to be similar to those for treating other painful conditions, whether the pain is categorised as acute or chronic.

These mechanisms have been researched extensively for over 60 years, and while there is still much left to learn about acupuncture mechanisms and the human body in general, the neural pathways from acupuncture point stimulation to the spinal cord and then to the deactivation of the pain centres in the brain have been mapped.89 Acupuncture has been demonstrated to activate a number of the body’s own opioids as well as improve the brain’s sensitivity to opioids.10 A number of other biochemicals involved in pain reduction have been found to be released and regulated by acupuncture stimulation, including ATP, adenosine, GABA and substance P.11 Acupuncture has also been demonstrated to reduce activity in the parts of the brain associated with the perception of pain and increase activity in brain areas associated with improved self-regulation.12[/vc_column_text][/vc_column][vc_column width=”1/3″][/vc_column][/vc_row][vc_row][vc_column width=”2/3″][dt_fancy_title title=”THE MAINSTREAM APPROACH TO TREATING CANCER PAIN” title_align=”left” title_size=”h3″ title_color=”accent”][ultimate_spacer height=”10″][vc_column_text el_class=”h2-line”]Analgesic drugs are the mainstay of pain relief, the main classes of which are non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen and opioids. These drugs are used singly or together according to the severity of pain.13 The most widely used guidelines for physicians about how best to provide pain management to their patients are those developed by the World Health Organization (WHO).  These include the 3-step analgesic ladder:

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Opioids

For moderate to severe cancer pain, opioids are the main choice. Despite wide-spread usage and recommendations from international guidelines, there remains a lack of high-quality studies to support their use. According to a recent review, “systematic reviews of the effectiveness of opioids in non-cancer pain show a paucity of literature of high quality RCTs with long-term follow-up and even appropriately performed non-randomized studies. Further, the literature on effectiveness of opioid therapy is even less in cancer survivors with chronic pain.”14 A recent Cochrane review providing an overview of Cochrane reviews for opioids for cancer pain highlighted the lack of data and commented that: “The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low,” and that “most people will experience adverse events.’15

Regarding the use of opioids to treat cancer pain in children and adolescents, a 2017 review concluded that “No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.’’16

The first and only randomized study to ever evaluate the long-term effectiveness of opioids for pain relief found that those taking opioids were actually in more pain at 12-months compared to those who were on non-opioid pain relief.17[/vc_column_text][/vc_column][vc_column width=”1/3″][vc_cta h2=”” css=”.vc_custom_1530036876358{background-color: #eeeeee !important;}”]”The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low.” Wiffen et al, Cochrane Database of Systematic Reviews, 2017 18[/vc_cta][/vc_column][/vc_row][vc_row][vc_column width=”2/3″][vc_column_text]

NSAIDs and Acetaminophen

For mild to moderate pain, NSAIDs and Acetaminophen (also known as non-opioids) are primary. Regarding side effects and safety, concerns about taking such painkillers have increased in recent years. A 2017 review of the safety of NSAIDs, which included 440,000 patients, found an increased risk of heart attack when using any NSAIDs at any dose, even for as little as one week.19 NSAIDs have also been shown to increase the risk of gastrointestinal bleeding,20 a serious and potentially fatal complication, as well as acute kidney injury.21 A 2016 systematic literature review of safety evidence found an increased risk of cardiovascular complications, GI bleeding, kidney toxicity and death from taking Tylenol or Paracetamol.22

Regarding the analgesic effectiveness of non-opioids, recent evidence from reviews is generally scarce. A 2017 Cochrane systematic review of Paracetamol for cancer pain in adults and children concluded, “there is no high-quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three-step WHO cancer pain ladder.23

A 2017 systematic review of NSAIDs for cancer pain in adults, which included adverse events associated with their use, concluded that there is no high-quality evidence to prove or disprove that NSAIDs are useful in treating people with cancer pain. Very low-quality evidence shows that some adults with moderate or severe cancer pain have their pain much reduced within one or two weeks of NSAID use.24 A similar review of evidence for treating cancer pain in children and adolescents (birth to 17 years) concluded that due to a lack of information (and the overall quality therefore being very low) there was no evidence to support or refute the use of NSAIDs to treat cancer pain in children and adolescents.25

Other pharmacological and non-pharmacological options for treating cancer pain

Other treatments for cancer pain include anti-depressants, anti-histamines, anti-anxiety medications, stimulants and amphetamines, anti-convulsants, steroids and complementary and alternative therapies;26 these treatments are subject to a lack of clinical data. Compared to pharmaceuticals, which are associated with adverse effects and suffer from a lack of clinical evidence of effectiveness to support their use, acupuncture is a safe, cost-effective and evidence-based treatment for cancer pain.[/vc_column_text][/vc_column][vc_column width=”1/3″][vc_cta h2=”” css=”.vc_custom_1530037354289{background-color: #eeeeee !important;}”]”There is no high-quality evidence to support or refute the use of NSAIDs alone or in combination with opioids for the three steps of the three-step WHO cancer pain ladder.” Derry et al 2017, Cochrane Systematic Review. 27[/vc_cta][/vc_column][/vc_row]

Acupuncture as a Therapeutic Treatment for Anxiety

Strength of evidence

Research suggests that between 1-30% of the global population suffers from some form of anxiety.1 There are 13 different sub-classifications of anxiety disorders listed in the latest Diagnostic and Statistical Manual (used by medical professionals to diagnose and treat psychological conditions),2 with symptoms and physical manifestations varying considerably. From shortness of breath and variations in heart rate, to full blown and debilitating panic attacks, headaches, pain and insomnia,3  anxiety is a complex, pervasive condition that is generally treated using medication.

 

According to the most up to date evidence, acupuncture is an effective treatment for anxiety. In 2017, The Acupuncture Evidence Project, co-authored by Dr John McDonald, PhD and Dr Stephen Janz,4 was published, providing an up-to-date comparative review of the clinical and scientific evidence for acupuncture. This comprehensive document, updating two previous reviews, determined that acupuncture is moderately effective in treating anxiety according to high level evidence.5 Their evidence included a 2016 systematic review with over 400 randomised patients that concluded that ‘the effects from acupuncture for treating anxiety have been shown to be significant as compared to conventional treatments.’6 The largest of these studies, which included 120 randomized patients, found that acupuncture had a large effect on reducing anxiety and depression compared to conventional treatment involving pharmalogical approaches and psychotherapy, with over twice the reduction in symptoms.7

 

A more recent systematic review published in 2018 found that all 13 included studies “reported an anxiety decrease for their treatment group relative to the control groups.” Three of these studies used pharmaceuticals as controls.8

Acupuncture for Anxiety PDF

You can download a PDF version of this summary here:


The autonomic nervous system (ANS), which is comprised of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS), regulates the internal conditions necessary for existence (homeostasis).(8) Information is received from the body and external environment and a response is delivered by either the SNS, which releases excitatory signals, or the PNS which releases signals for relaxation. These signals direct the body to react in very different ways, such as increasing the heart rate and contraction force, or by reducing blood pressure and slowing the heart rate.(9) It is exciting to know that studies show acupuncture has an effect on both the SNS and the PNS, as some further examples presented below reveal.

One of the most sensitive measures of the body’s ability to cope with stress is something called Heart Rate Variability (HRV). Rather than beating consistently at the same rate like a metronome, the heart actually changes its rate based on its fine-tuned response to the environment. A higher HRV has been associated with better health in all domains, including mental health and low levels of anxiety. Acupuncture has been shown to improve the body’s ability to cope with stress through improving HRV.(10)

When the body is under stress, an area of the brain called the hypothalamus releases neurochemicals,9 and research shows that acupuncture can calm this response.10

Acupuncture has also been shown to increase the release of endorphins,11 the body’s own ‘feel-good’ chemicals, which play  an important role in the regulation of physical and emotional stress responses such as pain, heart rate, blood pressure and digestive function.12 13 14 15

 

All of these acupuncture mechanisms have a direct effect on reducing anxiety.

 
 

The conventional treatment of anxiety primarily involves some combination pharmacological and psychological interventions.

 

PHARMACOLOGICAL APPROACHES

There are several medications that are prescribed for anxiety, including benzodiazepines (alprazolam), selective-serotonin re-uptake inhibitors (SSRIs) such as paroxetine, and tricyclic antidepressants (imipramine), either singularly or in combination.16 According to recent research, around 50% of patients treated pharmacologically for anxiety have an ‘inadequate response,’17 meaning that their symptoms are not alleviated to clinically significant levels or that the patient experiences adverse side effects. Some researchers go so far as to say that pharmacological treatments are ‘not ideal’ in terms of efficacy when employed for either short- and long-term treatment.18

 

Systematic reviews demonstrate that benzodiazepines can result in ‘sedation and drowsiness, mental slowing and anterograde amnesia’ (difficulty in forming new memories).19

 

BEHAVIOURAL APPROACHES

Cognitive behavioural therapy (CBT) and mindfulness-based CBT are two other popular and effective forms of conventional treatment for anxiety and may be prescribed as standalone therapies, or in combination with medications.20 CBT is a ‘talking therapy’ that aims to overcome inaccurate or negative thought patterns,21 and has the advantage of flexibility, where therapy is tailored to each individual and their relevant anxiety disorder. A meta-analysis found that compared to a placebo therapy, CBT had a moderate to large effect on reducing anxiety from a variety of causes.22

While there are ethical and methodological challenges to designing studies that compare the effectiveness of acupuncture to the conventional treatment of anxiety,23 24 the best available evidence demonstrates that acupuncture has moderate benefits in the treatment of anxiety. Studies show that acupuncture is more effective than pharmacotherapy and comparable to talking therapy, making it a helpful referral choice. Moreover, research has revealed several known biochemical and biophysical mechanisms that may offer an explanation of how this ancient modality works.

Kylee Junghans is a registered acupuncturist in private practice in Victoria, Australia. She has a Bachelor of Health Science (Acupuncture) and a Master of Public Health (Griffith University School of Medicine). She is the co-founder of the world’s largest online acupuncture research share group (almost 10,000 members).
Her areas of interest include pain management and mental health and she is passionate about developing the role of acupuncture in primary care in Australia.

References:

1. Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: a systematic review and meta-regression. Psychological Medicine. 2013; 43:897-910
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing. 2013
3. Health Direct. Anxiety symptoms .; . Available from: https://www.healthdirect.gov.au/anxiety-symptoms
4. McDonald J, Janz S. The Acupuncture Evidence Project: A Comparative Literature Review. Australian Acupuncture and Chinese Medicine Association Ltd. 2017.
5. Bazzan AJ, Zabrecky G, Monti DA, Newberg AB. Current evidence regarding the management of mood and anxiety disorders using complementary and alternative medicine. Expert Rev Neurother. 2014;14:411- 23.
6. Goyata SL, Avelino CC, Santos SV, Souza Junior DI, Gurgel MD, Terra FS. Effects from acupuncture in treating anxiety: integrative review. Rev Bras Enferm. 2016 Jun;69(3):602-9.
7. Arvidsdotter, T., Marklund, B., & Taft, C. (2013). Effects of an integrative treatment, therapeutic acupuncture and conventional treatment in alleviating psychological distress in primary care patients–a pragmatic randomized controlled trial. BMC Complementary and Alternative Medicine, 13(1), 308. http://doi.org/10.1186/1472-6882-13-308
8. Amorim, D., Amado, J., Brito, I., Fiuza, S. M., Clinical, N. A. T. I., 2018. (n.d.). Acupuncture and electroacupuncture for anxiety disorders: A systematic review of the clinical research. Elsevier. http://doi.org/10.1016/j.ctcp.2018.01.008
9. Abboud FM, Harwani SC, Chapleau MW. Autonomic neural regulation of the immune system: implications for hypertension and cardiovascular disease. Hypertension. 2012;59:755-62
10. Guo ZL, Longhurst JC. Expression of c-Fos in arcuate nucleus induced by electroacupuncture: relations to neurons containing opioids and glutamate. Brain Research. 2007;1166:65–76.
11. Ribeiro SC, Kennedy SE, Smith YR, Stohler CS, Zubieta JK. Interface of physical and emotional stress regulation through the endogenous opioid system and m-opioid receptors. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2005;1264-1280.
12. Harbach H, Moll B, Boedeker RH, et al. Minimal immunoreactive plasma b-endorphin and decrease of cortisol at standard analgesia or different acupuncture techniques. European Journal of Anaesthesiology. 2007; 24:370-6
13. Li M, Tjen-A-Looi SC, Longhurst JC. Electroacupuncture enhances preproenkephalin mRNA expression in rostral ventrolateral medulla of rats. Biol Psychiatry. 2010;477:61-5
14. Yin J, Chen J, Chen JDZ. Ameliorating effects and mechanism of electroacupuncture on gastric dysrhythmia, delayed emptying and impaired accommodation in diabetic rats. The American Journal of Physiology. 2010; 298:G563-G570
15. Agelink MW, Sanner D, Eich H, Pach J, Bertling R, Lemmer W, Klieser E, Lehmann E. Does acupuncture influence the cardiac autonomic nervous system in patients with minor depression or anxiety disorders? Fortschritte der Neurologie-Psychiatrie. 2003;71:141-9
16. Rickels K, Rynn M. Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry. 2002;63:Suppl 9-16
17. Generoso MB, Trevizol AP, Kasper S, Cho HJ,Cordeiro Q Shiozawa P. Pregabilnforgeneralizedanxietydisorder:an updated systematic review and meta-analysis. 2017;32:49-55
18. Baldwin D, Hou R, Gordon R, Huneke N, Garner M. GAD: experimental medicine models, emerging targets: Pharmacotherapy in generalized anxiety disorder: novel experimental medicine models and emerging drug targets CNS drugs .; .Available from https://eprints.soton.ac.uk/406180/
19. Perna G, Alciati A, Riva A, Micieli W, Caldirola D. Long-Term Pharmacological Treatments of Anxiety Disorders: An Updated Systematic.
20. Cuijpers P, Sijbrandij M, Koole S, Huibers M, Berking M, Andersson G. Psychological treatment of generalized anxiety disorder: A meta-analysis.Clinical Psychology Review. 2014; 34:130-140
21. Mayo Clinic. Cognitive behavioural therapy .; .Available from http://www.mayoclinic.org/tests-procedures/cognitive-behavioral-therapy/home/ovc- 20186868
22. Hofmann,S.G.,psychiatry,J.S.T.J.O.C.,2008.(n.d.).Cognitive-behavioral therapy for adult anxiety disorders:a meta-analysis of randomized placebo-controlled trials. Ncbi.Nlm.Nih.Gov
23. Hopton A, MacPherson H. Acupuncture for Chronic Pain: Is Acupuncture More than an Effective Placebo? A Systematic Review of Poled Data from Meta-analyses. Pain Practice. 2010; 10:94-102
24. Nardini C.The ethics of clinical trials. Ecancermedicalscience. 2014;8:387
References:
1. Chiu HY, Hsieh YJ, Tsai PS. Systematic review and meta-analysis of acupuncture to reduce cancer-related pain. Eur J Cancer Care. February 2016:n/a–n/a. doi:10.1111/ecc.12457.
2. Paley, C.A., Johnson, M.I., Tashani, O.A. and Bagnall, A.M., 2011. Acupuncture for cancer pain in adults. Cochrane Database Syst Rev, 1(10).
3. McDonald JL, Janz S. The Acupuncture Evidence Project. February 2017:1-81. http://www.acupuncture.org.au/OURSERVICES/Publications/AcupunctureEvidenceProject.aspx.
4. Chiu HY, Hsieh YJ, Tsai PS. Systematic review and meta-analysis of acupuncture to reduce cancer-related pain. Eur J Cancer Care. February 2016:n/a–n/a. doi:10.1111/ecc.12457.
5. Feeney C, Bruns E, LeCompte G, Forati A, Chen T, Matecki A. Acupuncture for Pain and Nausea in the Intensive Care Unit: A Feasibility Study in a Public Safety Net Hospital. The Journal of Alternative and Complementary Medicine. April 2017:acm.2016.0323. doi:10.1089/acm.2016.0323.
6. Lao L. Acupuncture practice, past and present: is it safe and effective? J Soc Integr Oncol. 2006;4(1):13-15.
7. Lu W, Dean-Clower E, Doherty-Gilman A, Rosenthal DS. The value of acupuncture in cancer care. Hematol Oncol Clin North Am. 2008;22(4):631–48–viii. doi:10.1016/j.hoc.2008.04.005.
8. Longhurst J, Chee-Yee S, Li P. Defining Acupuncture’s Place in Western Medicine. Scientia. February 2017:1-5.
9. Zhang Z-J, Wang X-M, McAlonan GM. Neural Acupuncture Unit: A New Concept for Interpreting Effects and Mechanisms of Acupuncture. Evidence-Based Complementary and Alternative Medicine. 2012;2012(3):1-23. doi:10.1016/j.brainresbull.2007.08.003.
10. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta J-K. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27(37):10000-10006. doi:10.1523/JNEUROSCI.2849-07.2007.
11. Zhao Z-Q. Neural mechanism underlying acupuncture analgesia. Progress in Neurobiology. 2008;85(4):355-375. doi:10.1016/j.pneurobio.2008.05.004.
12. He T, Zhu W, Du S-Q, et al. Autonomic Neuroscience: Basic and Clinical. Autonomic Neuroscience: Basic and Clinical. 2015;190(C):1-9. doi:10.1016/j.autneu.2015.03.006.
13. American Cancer Society. Non-opioids and Other Drugs Used to Treat Cancer Pain. cancer.org. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/pain/non-opioids-and-other-drugs-to-treat-cancer-pain.html. Published February 15, 2017. Accessed May 22, 2018.
14. Manchikanti L, Manchikanti KN, Kaye AD, Kaye AM, Hirsch JA. Challenges and concerns of persistent opioid use in cancer patients. Expert Review of Anticancer Therapy. 2018;7(1):1-14. doi:10.1080/14737140.2018.1474103.
15. Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain – an overview of Cochrane reviews. Cochrane Database Syst Rev. 2017;7:CD012592. doi:10.1002/14651858.CD012592.pub2.
16. Wiffen PJ, Cooper TE, Anderson A-K, et al. Opioids for cancer-related pain in children and adolescents. Cochrane Database Syst Rev. 2017;7:CD012564. doi:10.1002/14651858.CD012564.pub2.
17. Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain. JAMA. 2018;319(9):872–11. doi:10.1001/jama.2018.0899.
18. Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain-an overview of Cochrane reviews. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. 2017
19. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017;357:j1909-j1913. doi:10.1136/bmj.j1909.
20. Lanas A, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol. 2015;13(5):906–12.e2. doi:10.1016/j.cgh.2014.11.007.
21. Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015;26(4):285-291. doi:10.1016/j.ejim.2015.03.008.
22. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552-559. doi:10.1136/annrheumdis-2014-206914.
23. Wiffen PJ, Derry S, Moore RA, et al. Oral paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev. 2017;7:CD012637. doi:10.1002/14651858.CD012637.pub2.
24. Derry S, Wiffen PJ, Rev RMDS, 2017. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults. Wiley Online Library. doi:10.1002/14651858.CD012638.
25. Cooper TE, Heathcote LC, Anderson B, Grégoire M-C, Ljungman G, Eccleston C. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for Cancer-Related Pain in Children and Adolescents. Vol 25. (Cooper TE, ed.). Chichester, UK: John Wiley & Sons, Ltd; 2017:259–15. doi:10.1002/14651858.CD012563.
26. American Cancer Society. Non-opioids and Other Drugs Used to Treat Cancer Pain. cancer.org. https://www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/pain/non-opioids-and-other-drugs-to-treat-cancer-pain.html. Published February 15, 2017. Accessed May 22, 2018.
27. Derry, S., Wiffen, P. J., Rev, R. M. D. S., 2017. (n.d.). Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults. Wiley Online Library. http://doi.org/10.1002/14651858.CD012638