Understanding Pain and the Treatment of Chronic Pain
Understanding chronic pain and the task of its management can be quite a challenge, especially when dealing with patients suﬀering from cancer and other chronic debilitating illnesses. Pain is a subjective experience that encompasses more than just the physical component as generally understood by the medical profession. In palliative care, it is the “Total Pain” that is treated, which includes physical, emotional, psychosocial, and spiritual aspects of pain. Chronic pain is an unnecessary and unwanted suﬀering and the point is that it is manageable. It is important to treat this pain so that the quality of life can be improved. This signiﬁcance is relevant not only to the patient but also to the family. This article is a brief overview of the pathophysiology of pain, and its assessment and management.
GLOBOCAN estimates that about 14 million new cancer cases were diagnosed worldwide in 2012 and slightly more than 8 million cancer deaths occurred. One million of these new cases and nearly 700,000 of the deaths occurred in India, which is home to about 17% of the global population.[1,2]
Estimates of the prevalence of cancer pain have varied widely, mainly because of a lack of standardization in deﬁnitions of pain and in the measures used to assess it, due to the heterogeneity of nociceptive and neuropathic pain conditions, the heterogeneity of cancer diagnoses and various types of treatment settings in which the studies were conducted.
In general, the prevalence of pain at the time of cancer diagnosis in the early course of the disease, is estimated to be approximately 50%, increasing to 75% in later advanced stages.
One strategy for evaluating the prevalence of pain in cancer patients is to consider the following categories: pain related to the cancer, pain related to the treatment, or pain from unrelated causes.
These are discussed below:
(i) Pain Related to the Cancer
Tumors can impinge upon adjacent tissues, leading to pain. Although reports vary widely, the range of reported prevalence of pain is highest for the following tumors:[4-8]
- Head and neck (67–91%)
- Prostate (56–94%)
- Uterine (30–90%)
- Genitourinary (58–90%)
- Breast (40–89%)
- Pancreatic (72–85%)
(ii) Pain Related to the Treatment
Treatment-related pain may include painful peripheral neuropathy from chemotherapeutic agents such as vincristine, platinum, taxanes, thalidomide, bortezomib, and other agents; radiation-induced neural damage, including radiation-induced brachial plexopathy and post-radiation pelvic pain syndrome; and postsurgical pain syndromes from mastectomy, amputation, and thoracotomy.
(iii) Pain Unrelated to Cancer or its Treatment
People with cancer may develop pain that is not related to cancer, such as peripheral neuropathy from diabetes or pain after surgery for unrelated conditions.
Deﬁnition of Pain:
International Association for Study of Pain (IASP) deﬁnes pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” According to this deﬁnition, pain is not merely a physical experience but also emotional.
Pathophysiology of Pain:
The sensation of pain is the normal response to injury or damage from disease which results in activation of the pain receptors and the A delta and Type C pain ﬁbers. Pain is further classiﬁed as acute and chronic pain. Chronic pain is either due to ongoing injury resulting in persistent activation of the nerve ﬁbers or dysfunction of the nervous system (Figure 1). So, in chronic pain there is a sequence of events. The stimulation and sensitization of active nociceptors leads to recruitment of dormant nociceptors. There is sensitization of dorsal horn neurons and this further recruits the adjacent spinal segments. This results in muscle spasm and vasoconstriction which further worsen the pain intensity. Hence, it is recommended to treat chronic pain early.
Injury, inﬂammation, malignancy all increase the inﬂammatory mediators which serve as noxious factors that stimulate pain receptors and aﬀerent nerve ﬁbers, which then travel to the dorsal horn of spinal cord, and the impulse ascends in the spinothalamic tract to brain (Figure 2).
Concept of Total Pain:
Cecily Saunders, the founder of modern hospice care, coined the concept of ‘Total Pain”, to understand the complex nature of pain. It is the physical, social, psychological and spiritual components of pain (Figure 3). The contribution of each component will be speciﬁc in every individual. The experience of pain is also unique for every individual. Every patient’s description of pain will vary. The most important thing in the management of pain is to believe the patient. The concept of total pain goes beyond the IASP deﬁnition of pain and has an impact on the way we approach pain management.
A patient suﬀering from chronic pain might not appear to be suﬀering from pain, even if the pain is severe. He/she has gotten accustomed to the pain that one must live with. It is important to ask the patient about his pain. Sometimes, a patient may appear anxious, worried, or depressed instead.
Ask about the onset of pain, site, severity, radiation, aggravating and relieving factors, and quality of pain. Allow the patient to talk in his own language. Ask what this pain means to the patient, what are the coping mechanisms, what are the various drugs that have been used and found beneficial.
A detailed history is helpful to understand the complexity of pain; its psychosocial and spiritual dimensions and to chalk out a holistic treatment plan.
Features of Neuropathic Pain:
- Pain is in an area of absent or abnormal sensation
- Pain is usually burning, pricking, aching, shooting/radiating, lancinating in nature
- Neural/dermatomal distribution is seen
- Abnormal sensations like allodynia and paraesthesias may be present
- May be peripheral or central
Diabetic neuropathy, stroke and spinal cord injuries result in neuropathic pain.
History taking for pain needs to be done in detail. Use of the mnemonic “OPQRSTU” can help in determining the cause and type of pain, and which medication might be useful.
Onset of the event
What the patient was doing when it started (active, inactive, stressed), whether the patient believes that activity prompted the pain, and whether the onset was sudden, gradual or part of an ongoing chronic problem.
Provocation or Palliation
Whether any movement, pressure (such as palpation) or other external factor makes the problem better or worse. This can also include whether the symptoms relieve with rest.
Quality of the pain
This is the patient’s description of the pain. Questions can be either open ended such as “Can you describe it for me?” or leading. Ideally, this will elicit descriptions of the patient’s pain; whether it is sharp, dull, crushing, burning, tearing, or some other feeling, along with the pattern, such as intermittent, constant, or throbbing.
Region and Radiation
The location of the pain on the body and whether it radiates to any other area. This can give indications for conditions such as a myocardial infarction, which can radiate through the jaw and arms. Other referred pain can provide clues to underlying medical causes.
The pain score (usually on a scale of 0 to 10).
Zero is no pain and ten is the worst possible pain.
This can be comparative (such as “… compared to the worst pain you have ever experienced”) or imaginative (“… compared to having your arm ripped oﬀ by an alien”). If the pain is compared to a prior event, the nature of that event may be a follow-up question. The clinician must decide whether a score given is realistic within their experience – for instance, a pain score 10 for a stubbed toe is likely to be exaggerated.
This may also be assessed for pain now, compared to pain at time of onset, or pain on movement. There are alternative assessment methods for pain, which can be used when a patient is unable to vocalise a score. One such method is the Wong-Baker faces pain scale used in children.
Ask the patient “How long has the condition has been going on? How has it changed since onset (better, worse, diﬀerent symptoms)? Has it has ever happened before? How has it changed since onset? Has the pain has stopped?
Understanding and Impact
Ask the patient “What do you believe is causing this? How is the pain aﬀecting your activities of daily living (ADL)? How is it aﬀecting your family? Do you have any other concerns?”
Once a detailed history is obtained it is important to quantify pain. This can be done using various tools/scales (Figure 4) that measure pain. It would be important to use the appropriate scale for the setting or type of patient such as the Wong-Baker FACES rating scale is used in paediatrics due to its visual description making it easily understood by paediatric patients (Figure 5).
- Hyperesthesia: an abnormal increase in sensitivity to normal stimuli.
- Hyperalgesia: an increased sensitivity to pain which is caused due to damage to nociceptors.
- Allodynia: is central pain sensitization (increased response of neurons) following non-painful, often repetitive stimulation.
- Dysthesia: an unpleasant, abnormal sense of pain (itchy, burning or restrictive sensation) caused by nerve damage. Associated mostly with neurological conditions such as multiple sclerosis.
- Paraesthesia: an abnormal sensation (typically tingling or pricking) caused chieﬂy by pressure on a damage to peripheral nerves.
- Analgesia: lack of pain.
- Anaesthesia: lack of sensation.
Factors Modulating Pain
- Meaning of pain
Pain is increased when certain conditions or factors are present such as insomnia, fatigue, negative emotions, fears of social isolation/abandonment. On the other hand, certain factors decrease pain such as adequate sleep, control of other symptoms, having someone to share and understand (companionship), relaxation and creative activity.
Diﬀerent Types of Pain:
Baseline Pain which may be continuous or intermittent.
Breakthrough Pain: a sudden increase in moderate to severe pain, of short duration (spikes).
End of Dose Pain: pain that occurs prior to the next due dose, gradual in onset and lasts longer.
Principles of Pain Management
- Diagnose the cause of the pain
- Full assessment of all contributing factors
- Explain the mechanism underlying the pain to the patient
- Set treatment goals
- Use the WHO analgesic step ladder (Figure 6) to guide medication use for systematic pain relief
- Consider other treatments modalities (surgery, nerve blocks, radiotherapy and non-drug treatments) which may also have a role.
Approach to Management of Pain:
The earlier the pain is treated, lesser will be the self-perpetuating changes. Continuous pain needs continuous analgesia. Untreated pain aﬀects the morale of the person and the family, leads to unnecessary stress, loss of sleep, fear and worsening of pain.
- Chemotherapy (Palliative)
- Radiotherapy (Palliative)
- Interventional pain treatment such as spinal/epidural analgesia/blocks
- Relaxation therapy, Aromatherapy
- Massage therapy
- Acupuncture, Acupressure
Medications for Pain Management:
Step 1: Paracetamol and Nonsteroidal Anti- Inﬂammatory Drugs (NSAIDs) are indicated. Paracetamol is given as 500-650 mg every 4-6 hours. NSAIDs inhibit cyclooxygenase (COX), an important enzyme in the arachadonic acid cascade. This inhibits prostaglandin synthesis contributing to the anti-inﬂammatory action. NSAIDs are classiﬁed depending on which COX form (i.e. COX-1 or COX-2) is inhibited.
Rationale for prescribing NSAIDs
Select the safest drug for each patient
Select the lowest but eﬀective dose which will be needed for the shortest period of time
Prescribe gastro-protective medications
A description of the various NSAIDs is given below (Table 1 ).
Pharmacokinetics of NSAIDs:
Most are absorbed completely and have negligible ﬁrst-pass metabolism. They undergo hepatic metabolism by CYP-2C8, 2C9, 2C19 and/or glucoronidation. They are tightly bound to serum proteins. Short acting (less than 6 hours) are ibuprofen, diclofenac, and indomethacin. Long acting (more than 6 hours) are naproxen, meloxicam, and piroxicam (Tables 2 & 3).
Opioids are classiﬁed as weak and strong opioids. Tramadol and tapentadol fall in the weak opioids category.
It is a synthetic centrally acting analgesic with both opioid and non-opioid action. It is a codeine derivative and is also structurally related to venlafaxine (NSSRI). Its mechanism of action is by presynaptic inhibition of re-uptake of serotonin and norepinephrine (analgesic action) and it also has an agonistic action on the µ-opioid receptor. Tramadol also signiﬁcantly improves neuropathic pain. Advantages of tramadol over morphine is that it causes less constipation and respiratory depression as equi- analgesic doses of morphine. Its dependence liability is considerably less. Only limiting factor with higher doses is dizziness and vomiting. The analgesic eﬀect of tramadol is reduced by ondansetron (possibly due to blocking of serotonin at the presynaptic 5HT receptors). Maximum recommended dose of Tramadol is 400 mg per day.
It is a centrally acting analgesic with a dual mode of action; a µ-opioid receptor agonist and a norepinephrine reuptake inhibitor (SNRI). The analgesic action has been compared to tramadol and its potency ranges somewhere between that of tramadol and morphine. No dose adjustments are required in patients with mild hepatic impairment, however in moderate impairment the dose is reduced to 50 mg every 8 hourly. It is not recommended in severe hepatic impairment. No dose adjustments are required in mild to moderate renal impairment. Bioavailability is 32 % and pharmacokinetics are given below (Table 4). The initial starting dose is 25-50 mg 8 hourly, however this dose can be increased to 50-100 mg every 4-6 hours if needed. Maximum daily dose is 600 mg per day.
When pain does not respond to a combination of a non-opioid and a weak opioid (as in Step 2), then morphine is the next alternative. It is considered the gold standard in palliative pain treatment. As per the WHO stepladder, all Step 3 opioids such as morphine, must be combined with Step 1 analgesics. Morphine has a wide variability in bioavailability from 15% to 60% when given orally. Pharmacokinetics are given in Table 5. Due to side eﬀects of nausea and constipation, an anti-emetic (metoclopramide, ondansetron, haloperidol) and laxative (bisacodyl, cremaﬃn) should be prescribed routinely.
When prescribing morphine, lower doses should be started ﬁrst and then slowly titrated upwards if no relief with lower doses. Breakthrough doses should be given SOS. for pain. If there are many breakthrough doses that are required, then a recalculation of the daily dose needs to be done as it indicates poor control of the pain. This is done by totaling the amount of morphine taken as breakthrough doses and added to the previous daily dose. This amount is then divided and given as the new daily dose. It is also recommended to double the nightly dose if there is pain at night and the patient is waking up or unable to sleep. The double dose obviates the need to take the 2 am dose. Due to its short half-life, dosing must be repeated on a frequent basis (every 4 hours in general). The frequency must however be decreased in hepatic and renal failure patients due to the accumulation of an active metabolite. Morphine is available as immediate release (IR) and sustained release (SR) preparations.
Initial: Dosing with immediate release/normal release (IR) Morphine
Start with a low dose morphine (5mg if opioid naïve or 10 mg if opioid tolerant) given every 4 hours with SOS doses if required. After 1-2 days, recalculate the daily dose depending upon total (4-hourly doses + SOS doses) used in previous 24-hours and then divide by 6. If required, keep on increasing the regular dose until there is adequate relief throughout the day. Double the dose at bedtime. Titration of morphine helps to minimise side eﬀects.
Later: May replace with sustained release (SR) morphine
Once the morphine daily dose has been determined to give adequate pain relief and dose amount is stable, then replace with SR every 12-hourly. If SOS doses are required, these should be with the normal release morphine which should be 1/6th of the daily dose or the same as the 4- hourly dose.
Fentanyl is a low molecular weight µ receptor agonist with lipophilic properties hence it has transdermal and transmucosal permeability. It also gets sequestered in body fat and central nervous system white matter. It has a steady state plasma concentration of 36-48 hours. It is inactivated in the liver by CYP 3A4 enzyme into norfentanyl. The onset of action, time to peak eﬀect and duration of action depends on the mode of administration (Table 6).
Instructions to Patients Using a Fentanyl Patch:
- Recommended sites should be dry, non-hairy, As per the IASP classiﬁcation, neuropathic ﬂat surfaces of the body, with normal skin such as upper chest or arm.
- Avoid inﬂamed or irradiated skin areas.
- Patch should be applied without any wrinkling and continuous contact with the skin ensures eﬃcacy.
- Do not remove and reapply the same patch or cut the patch to halve the dose
- Do not apply hot fomentation to the patch or take hot tub baths. A hot shower is ﬁne
Methadone is a synthetic opioid which is a µ- receptor agonist, also possibly a delta-opioid receptor agonist, an NMDA-receptor channel blocker, and a presynaptic serotonin re-uptake blocker. Initially, was used as a maintenance drug for treatment of opioid addiction, now it is indicated if the pain is poorly responsive to morphine and other step 3 opioids. It is also indicated if there is severe neuropathic pain as well as if there is renal impairment.
Diﬃculties of using methadone are that it has a complicated dosing due to a wide, variable plasma half-life. It can cause prolonged QT interval and cardiac arrhythmias.
Adjuvant Analgesics for Neuropathic Pain:
Adjuvants are drugs used in the management of pain conditions that are otherwise diﬃcult to treat. They act as add-on drugs to other pain medications and by themselves they are not analgesics.
Majority of neuropathic pain conditions respond well to the systematic use of non- opioids, opioids and adjuvant analgesics. However, in some cases, other interventions like spinal analgesia or transcutaneous electric nerve stimulation (TENS) may need to be done.
As per the IASP classification, neuropathic pain is pain caused by a primary lesion or dysfunction in the nervous system and is classiﬁed as peripheral (when the cause lies in the peripheral nervous system) or central (central nervous system).
Adjuvants are commonly used depending on the site of action and its indications (Table 7).
Hence the use of adjuvants depends on the etiology, type of pain, and site of pain. The use of adjuvant analgesics for neuropathic pain if caused by cancer, should only be used if the pain does not respond to the combination of non- opioid and strong opioid (Step 3 of the WHO pain ladder).
The manner of use of these adjuvants is graded in a step-wise manner so that one can start with the lower step and progress upwards based on whether analgesia is achieved or not. Approach should be simple and should progress upwards using only one or two drugs from each category as needed. The patient must be informed that full beneﬁt may sometimes take over a week. Dose escalation must be done slowly to avoid excessive side eﬀects. Response seen by the patient will be initially an improvement in sleep and longer intervals of pain-free or lower intensity pain rather than having no pain around the clock.
Step 1: Corticosteroids
Step 2: Tricyclic Antidepressants (TCA’s) or Anticonvulsants
Step 3 – Tricyclic Antidepressants and Anticonvulsants
Step 4 – NMDA receptor blockers
Step 5 – Spinal analgesia
Patients need not suﬀer or die in any pain. All medical practitioners must be aware of the need to treat pain and to be able to manage it. In pain management, what we observe is only the tip of the iceberg if we concentrate only on the physical aspect. It is important to understand pain in its totality; only then can we eﬀectively provide pain relief.
- Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No.11. Lyon, France: International Agency for Research on Cancer ; 2013. Available from : http://globocan.iarc.fr/Pages/fact_sheets_c ancer.aspx
- Mallath MK, Taylor DG, Badwe RA, Rath GK, Shanta V, Pramesh CS, et al. Cancer burden and health systems in India. The growing burden of cancer in India : epidemiology and social context. Lancet Oncol. 2014; 1-8.
- Epidemiology of Cancer Pain. Global Year Against Cancer Pain. International Association for the Study of Pain. Oct 2008. Available from: www.iasp-pain.org
- Higginson IJ, Hearn J. A multi-centre evaluation of cancer pain control by palliative care teams. J Pain Symptom Manage 1997; 14:29-35.
- Jarlbaek L, Hallas J, Kragstrup J, Andersen M. Cancer patients’ ﬁrst treatment episode with opioids: a pharmaco-epidemiological perspective. Support Care Cancer 2006; 14:340-7.
- Potter J, Higginson IJ. Pain experienced by lung cancer patients: a review of prevalence, causes and pathophysiology. Lung Cancer 2004; 43:247-57.
- Valeberg BT, Rustoen T, Bjordal K, Hanestad BR, Paul S, Miaskowski C. Self-reported prevalence, etiology, and characteristics of pain in oncology outpatients. Eur J Pain 2008; 12:582-90.
- van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18:1437-49.
- Wong-Baker FACES Pain Rating Scale; www.WongBakerFACES.org
- World Health Organisation. Cancer Pain Relief. WHO, Geneva. 1986. Available at:www.who.int/cancer/palliative/painladder/enstepladder
- IASP Task Force on Taxonomy. Classiﬁcation of Chronic Pain. IASP Press: Seattle. 1994.
- Twycross R. Introduction to palliative care. 4th edition. United Kingdom: Radcliﬀe Medical Press. 2003.