Pain and Endocrine Disease: Diabetes Mellitus

Pain Associated with Medical Diseases

• Pain is a sign of disease, and the pain sensory system detects tissue-damaging processes to protect the body's homeostasis.
• Pain is a common symptom that leads patients to seek medical advice.
• Treatment should aim to limit the disease to alleviate pain.
• In cases lacking definitive treatment, such as HIV, chronic pain persists despite correct diagnosis.
• Pain management improves overall patient care and quality of life.
• Different diseases producing different pain syndromes require an understanding of pathophysiology for proper management.

Pain and Endocrine Disease: Diabetes Mellitus

• Diabetes mellitus (DM) affects multiple organ systems, including the cardiovascular, renal, peripheral nervous system, and eye.
• Physicians in pain clinics often care for diabetic patients with diabetic peripheral neuropathic pain (DPNP) or peripheral vascular disease and related complications.
• Diabetic peripheral neuropathy (DPN) is characterized by peripheral nerve dysfunction signs and symptoms in DM patients, excluding other causes.
• Pain associated with DPN significantly impairs quality of life, even if most DPN patients do not experience pain.
• The pathophysiology of diabetic neuropathy remains unclear.
• The incidence of DPN is more frequent with increasing age, DM duration, and severity/duration of exposure to hyperglycemia.
• The pathogenesis of diabetic neuropathy is multifactorial, with proposed mechanisms that include:
  • Activation of the polyol pathway with resultant reduction in Na+/K+-ATPase activity.
  • Non-enzymatic glycation causing glycosylation and changes in nerve fiber proteins.
  • Hyperglycemia resulting in poor blood supply to and infarction of the nerves via activation of protein kinase C.
  • Reduced blood supply to nerve fibers causing oxidative stress and free radical formation.
  • Auto-immune mechanisms
  • Nerve growth hormone(neurotrophins) deficiency leading to axonal atrophy.

Clinical Features of DPN

• Diabetes-associated neuropathies manifest as generalized symmetrical polyneuropathies and focal or multifocal neuropathies.
• Both small and large nerve fibers can be affected in DPN, impairs sensory and motor function; motor function impairment is usually mild.
• Diabetic peripheral neuropathy is insidious, affecting feet/lower limbs first, then hands, in a "stocking and glove" distribution.
• DPN symptoms may be spontaneous/evoked and worse at night.
• Pain occurs in 11–20% of DPN cases.
• Clinical features indicating autonomic neuropathy include:
  • Tachycardia
  • Painless myocardial infarction
  • Orthostatic hypotension
  • Oesophageal dysfunction
  • Gastroparesis
  • Diarrhea
  • Constipation
  • Incontinence
  • Erectile dysfunction
  • Neurogenic bladder
  • Dry and warm feet

Diagnosis and Management of DPN

• Physical examination, including muscle power and sensation, is essential.
• Nerve conduction study changes in diabetic neuropathy are non-specific.
• Nerve conduction studies aim to exclude other differential diagnoses.
• Nerve conduction velocity diminishes gradually in diabetic neuropathy.
• Management of DPN includes disease modification, symptomatic relief, and prevention of complications.
• Disease modification involves secondary preventive measures, including treatment of hypertension and hyperlipidaemia and good glycaemic control.
• Disease modification can substantially reduce the risk of developing complications and slow their progression in all DM types.
• Diet, exercise, and oral hypoglycaemic agents/insulin administration are involved with disease modification.
• Drug treatment is ranked in three tiers for symptomatic relief:
  • First-tier agents: duloxetine, pregabalin, oxycodone CR.
  • Second-tier agents: carbamazepine, gabapentine, lamotrigine, tramadol, venlafaxine ER.
  • Other: topical agents, bupropion, citalopram, paroxetine, phenytoin, topiramate, methadone.
• To prevent complications it is important to manage foot ulcers in DPN patients.

Pain and Cardiovascular Diseases: Peripheral Arterial Disease

• Peripheral arterial disease (PAD), also known as arteriosclerosis obliterans, is the chronic obstruction of arteries supplying the lower extremities
• PAD is is the peripheral arterial manifestation of generalized atherosclerosis
• The pain mechanism due to ischemia remains undetermined, but suggested mechanisms include: -Putative nociceptive fibres mediate ischaemic pain -Accumulation of metabolites causes sensitization of peripheral nociceptors -Involvement of "mechanical determinants" of the nociceptors during ischaemia -A central mechanism leading to a chronic pain state.
• A neuropathic pain mechanism may also play a role, especially in patients with diabetes, commonly associated with PAD

Classification of PAD

• Acute peripheral arterial events classification:
  • Aortic events includes ruptured or acute symptomatic aortic or iliac aneurysm, or thoracic aortic dissection
  • Acute thromboembolic events include limbs or viscera conditions.
  • Critical limb ischaemia includes: lower limb intermittent claudication, rest pain, skin ulcer, and gangrene. 90% of patients with severe limb ischaemia end up with amputation.
• Chronic critical limb ischaemia is defined as ischaemic rest pain and ischaemic ulcers or gangrene
• Fontaine classification of chronic leg ischaemia:
  • Stage I: Asymptomatic
  • Stage II: Intermittent claudication
  • Stage III: Ischaemic rest pain
  • Stage IV: Ulceration or gangrene, or both

Management of PAD

• Disease modification includes: smoking cessation, exercise rehabilitation, optimizing hyperlipidaemia control, optimizing hypertension control
• Cilostazol, a phosphodiesterase III inhibitor with vasodilator and antiplatelet activity is helpful for disease modification
• Iloprost, a prostacyclin analogue, and prostaglandin E1 have been found to reduce pain.
• Anti-platelet agents: aspirin, Clopidogrel is an alternative for patients who do not tolerate aspirin
• Invasive interventions: endovascular stenting, percutaneous transluminal balloon angioplasty and open surgical bypass or endarterectomy should be considered for suitable patients to improve the blood supply to the lower limbs.
• Pain control
• Lumbar sympathectomy
• Spinal cord stimulation
• WHO analgesic ladder is advisable for pain control.
• It is necessary to remember that neuropathic pain may be associated with PAD and analgesia specific for neuropathic pain should always be considered when managing these patients
• If pain becomes intractable or intolerable side effects develop from analgesics, interventional pain therapies such as lumbar sympathectomy, and spinal cord stimulation should be considered.

Pain and Cardiovascular Diseases: Coronary Artery Disease

• Angina is described as substernal chest pain associated with squeezing, tightness, aching, dullness, fullness, heaviness or pressure, typically aggravated by exertion or emotional stress
• Reduced blood supply to the myocardium because of coronary atherosclerosis, spasm, or a combination of both leads to myocardial ischaemia and usually manifests as angina pectoris.
• Anginal pain is primarily nociceptive and arises from the adventitia of the coronary arteries and the myocardium.
• Afferent impulse travels along the sympathetic nerves to the upper four thoracic sympathetic ganglia and continues to enter the TI-T6 spinal cord segments
• Angina serves as a warning sign to patients, reduction in activity will limit the severity of the ischaemic injury
• The management of angina includes : anti-ischaemic therapy, anti-platelet/anticoagulant therapy, risk factor modification, and revascularization
• Optimal standard therapy includes administration of a betablocker and calcium channel blocker to achieve the lowest heart rate and after-load reduction.
• A long acting nitrate and angiotensin-converting enzyme inhibitor are also recommended.
• Aggressive risk factor modification, such as smoking cessation, cholesterol-modifying agents, and exercise training are essential
• Symptomatic control includes when medical treatment is optimized and surgical treatment is not an option, symptomatic relief becomes the only possible treatment; Morphine is commonly included in the management of angina and a weak opioid like tramadol can be successful in symptomatic control

Pain and Cardiovascular Diseases: Non-Cardiac Chest Pain

• Non-cardiac chest pain (NCCP) is defined as chest pain not due to cardiac ischaemia or other major physical disorders
• Causes of non-cardiac chest pain include:
  • Gastrooesophageal reflux disease
  • Visceral hypersensitivity
  • Psychological origin
  • Oesophageal dysmotility, altered central processing of oesophageal stimuli and autonomic dysregulation, etc.

Pain and Infectious Diseases: Human Immunodeficiency Virus Disease

• The human immunodeficiency virus (HIV) is a retrovirus that infects the body's immune cells, leading to a decline in defenses against disease.
• Clinical features of HIV-infected patients correlate with the CD4+Tcell count.
• Patients are generally asymptomatic when CD4 count >500cells/mm3 and When the CD4 count is <200 cells/mm3, a range of opportunistic infections and unusual malignancies can manifest.
• Pain is the most common symptom in stage 4 AIDS patients with 98% prevalence, usually of more than one type, more than one location, and increases in intensity as the disease progresses.
• The mechanism of pain in HIV/AIDS is multifactorial with diverse aetiologies.
• Nociceptive pain can be secondary to combinations of inflammation, including autoimmune responses, infection especially opportunistic infection, and neoplasms such as lymphoma or Kaposi's sarcoma.
• Neuropathic pain in HIV/AIDS patients secondary to neuropathy is common with a prevalence of up to 50% and can be due to direct HIV viral infection to the central or peripheral nervous system; secondary infection by other pathogens; immune-mediated demyelination; and neurotoxicity secondary to HAART, alcohol, nutritional deficiency and/or other drugs such as antimycobacterials and antineoplastics
• Gastrointestinal pain syndromes, pain can arise anywhere along the gastrointestinal tract including the oral cavity, oesophagus, anus and rectum.
• Candida infection is the most common cause of pain in the oral cavity and oesophagus, followed by ulcers from a variety of organisms, necrotising and ulcerating infections.
• Infectious causes of chest pain include Pneumocystis pneumonia, oesophagitis, pleuritis, pericarditis and postherpetic neuralgia.
• Kaposi's sarcoma and lymphoma are the common neoplastic causes of chest pain.
• Differential diagnosis for headache in patients with HIV includes HIV encephalitis and atypical aseptic meningitis, opportunistic infections AIDS-related central nervous system neoplasm, sinusitis, tension, migraine and azidothymidine (AZT).
• Neuropathy is symmetrical predominantly sensory painful peripheral neuropathy; known as distal sensory polyneuropathy (DSP) which occurs in about one third of all HIV-infected patients. The most likely mechanisms of DSP are immunological dysfunction secondary to HIV, and the neurotoxic effects of antiretroviral drugs.
• Several types of painful arthritis and arthropathies have been reported with HIV/AIDS, non-specific arthralgia, reactive arthritis, psoriatic arthritis, HIV-associated arthritis, aseptic arthritis, with Reiter's syndrome. Muscle pain is due to myopathy and polymyositis, which may be secondary to HIV infection or antiretroviral therapy.
• HIV pain is considered to be similar to cancer pain.
• The management of cancer pain can also be applied to the management of AIDS-related pain.
• A pharmacological approach following the WHO analgesic ladder using opioids and co-analgesics is the mainstay of treatment for end-stage AIDS patients when disease specific therapy is not available.

Pain and Haematological Disorders

• Haemophilia is a sex-linked genetic coagulation disorder due to qualitative or quantitative defects of clotting factors.
• Although all clotting factors can be affected, defect in Factor VIII (haemophilia A) and Factor IX (haemophilia B) are the most common inherited coagulation disorders.
• The severity of haemophilia depends on the plasma concentration of clotting factor and is graded as severe if the concentration is less than 1%.
• The major complication of haemophilia is intraarticular bleeding to the large joints leading to repeated haemarthrosis, chronic synovitis, epiphyseal overgrowth, destruction of cartilage and eventually joint deformity in the adolescent.
• The pain and joint deformity have a profound effect on the function and quality of life for haemophilia sufferers
• Management includes disease can be modified with prophylactic factor replacement, corticosteroids, non steroidal anti-inflammatory drugs and medical prophylaxis.
• The disease process can be modified with prophylactic factor replacement to maintain plasma factor level > 1% between I and 3 years of age to prevent joint destruction
• Corticosteroids have been used to decrease synovium in chronic synovitis with good but temporary results.
• Non steroidal anti-inflammatory drugs have a limited role in this situation due to the associated risk of bleeding.
• In situations where medical prophylaxis is not possible, such as unavailability of factor product or development of inhibitors to transfused product, open or arthroscopic surgical synovectomy can effectively retard the pathological process of haemophilic arthropathy.
• Intra-articular injection of chemical or radioisotope sclerosing agent has been used as the alternative for surgical synovectomy and found to have short-term effect
• Total joint replacement may be the ultimate procedure for haemophilic arthropathy and can bring considerable improvement in joint movement and pain relief
• physical therapy
• Sickle cell disease is an inherited haemoglobin disorder.
• Chronic haemolytic anaemia occurs in homozygous inheritance of haemoglobin S characterised by the sickle-shaped red blood cells causing vasoocclusion and infarction.
• Throughout their lives the homozygotes are affected by recurrent painful episodes which are highly variable in frequency and severity among patients
• Interventions recommended to modify the disease processes from childhood to avoid permanent damages include:
  • Prophylactic antibiotics with daily penicillin V potassium from 2 months of age until age 5 years;
  • Childhood immunisation with 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide pneumococcal vaccine for children less than 2 years and older than 2 years respectively;
  • Hydroxyurea, which can increase haemoglobin F levels and improve red cells deformability, should be considered for those who have frequent severe painful episodes.
  • Aggressive and early pain control according to the WHO analgesic ladder.
  • Morphine is the first choice of opioid analgesic and patient-controlled analgesia is recommended if facilities are available.
  • Non-pharmacological pain management such as psychological and physical approaches are beneficial.
  • Other general measures, such as rehydration, oxygen supplement, antibiotics and blood transfusion if indicated.

Pain and Pancreatic Disorders

• Acute pancreatitis is a disorder of the pancreas caused by an intracellular activation of pancreatic digestive enzymes, and is managed based on vital signs, fluid replacement, electrolyte disturbance, nutritional support, prevention of complications and pain relief.
• As acute pancreatitis is accompanied by persistent severe pain analgesia is crucial in managing patients with acute pancreatitis. Buprenorphine is often recommended.
• Chronic pancreatitis (CP) is a progress of the pancreas leading eventually over years to fibrotic destruction of the pancreas resulting in exocrine and endocrine insufficiency.
• Pain is a prominent symptom and and at least 85% of patients with CP will develop pain at some time during the course of the disease
• No definitive treatment to counteract the inflammatory process pain control becomes an important element in the management of CP.
• Early-stage CP is characterised by recurrent attacks of acute pancreatitis.
• The early stage may last for several years and is followed by the late-stage CP with development of chronic pain, pancreatic calcifications and pancreatic insufficiency.
• Abdominal pain is typically worsened after a meal, limits the food intake and contributes to weight loss and malnutrition.
• Two types of pain in CP have been described:
  • A-type pain which include short relapsing pain episodes which last for 2 to 10 days and separated by long pain-free periods of months (or years): this pain can be linked to initiation of alcoholic CP
  • B-type pain includes prolonged periods of either persistent (daily) pain or clusters of recurrent severe pain exacerbations which last for at least 2 months and require repeated hospitalisation; pain often associated with local complications, such as pseudocysts or obstructive cholestasis
• The course of pain in CP remains unpredictable and highly variable, but spontaneous partial or complete pain relief in latestage CP is common.
• Important management steps include abstinence from alcohol and smoking, supportive therapy for exocrine and endocrine insufficiency and pain control.
• Other management steps include pancreatic enzyme supplementation, elevation of duodenal pH with cimetidine or proton pump inhibitors and somatostatin analog octreotide to reduce pancreatic enzyme secretion and thereby reduce pain.
• When avoidance of precipitating factors and other general measures fail to provide pain relief, a pharmacological approach using the WHO analgesic ladder is recommended.
• All opioids will increase the sphincter of Oddi pressure, it is thought that the benefits of morphine may outweigh its risk in treating pancreatitis.
• Radiological examination of the pancreatic morphology is recommended where the pain becomes intractable, in the setting of increasing pain (type-B pain).
• Treatments such as Endoscopic intervention, denervation procedures or surgical therapy are sometimes necessary.
• Endoscopic interventions such as; stent placement, stone extraction, stricture dilatation and pancreatic sphincterotomy (were found to be beneficial in patients with large duct and ductal hypertension )

Pancreatic Cancer

• The majority of patients have metastasis or advanced local disease at the time of presentation and are unresectable, palliative management of symptoms becomes the prime concern.
• The three main symptoms in pancreatic cancer are pain, weight loss, and jaundice.
• The presence of pain has been shown to have an inverse correlation with survival
• Neurolytic coeliac plexus block can be used for pain control which shows improvement in quality of analgesia and reduces opioid requirement but has had no effect on survival
• Bilateral thoracoscopic splanchnicectomy has been shown to significantly reduce the mean pain score

Visceral Pain

• Visceral pain may arise from any internal organs within the thorax, abdomen or pelvis
• It is a type of nociceptive pain
• Visceral sensory neurons are responsible for detecting chemical, thermal and mechanical stimuli, and can be sensitised by local ischaemia, hypoxia and the consequent release of inflammatory mediators after local inflammation or tissue injury
• Pain arising from viscera can be due to an underlying pathological process, or is deemed "functional” when no identifiable cause is found.
• Treatment of organic visceral pain should be directed to the underlying cause, whereas a multidisciplinary approach is needed to manage visceral pain that is functional in origin
• It may be felt if there is an infection, trauma, disease, a growth, bleeding causing pressure, inflammation,
• The sensory nerves in organs have pain receptors called nociceptors that alert the body to the condition
• The sensory nerves signal the awareness from compression,stretching, tearing or tiny area of damage
• Unlike superficial pain, visceral pain tends to radiate from the initial location to involve other areas of the body as well, making the whole pain experience more diffuse and unpleasant
• Visceral referred pain can be felt in nearby areas of the body instead of in the injured area itself, making it difficult to pinpoint where it is coming from
• Other symptoms may accompany visceral pain such as nausea, sweating, paleness, and changes in blood pressure, heart rate, and temperature

Abdominal Pain

• There are four basic sources of abdominal pain including visceral, somatic, referred and chronic pain post abdominal surgery
• Visceral pain usually comes from hollow organs and is elicited with distension, compression, or torsion of an organ
• Unlike other pain types, cutting a visceral organ like the intestines during surgery is not painful
• Visceral pain is not well localised and often described as dull and achy, it has small numbers of visceral afferent nerves covering large areas.
• Somatic pain comes from abdominal cavity structures
• The pain is often well localized
• A common aggravating factor is movement
• This type of pain has neuroma which can entrap a branch of the anterior cutaneous nerve as it courses through the abdominal wall muscle.
• Chronic pain post abdominal surgery manifests up to 90% of surgery goers
• The pain can vary depending where the adhesion is affecting, with adhesion above the liver related to breathing and adhesions close to the small intestines related to obstruction
• Referred Pain occurs when the brain becomes confused and interprets pain as coming not from the actual pain generator but rather from another source that happens to enter the spinal cord at the same level
• Treatment for Chronic abdominal pain is treated in the outpatient setting medically with lifestyle modification, nonopioids, and opioids depending based on the diagnosis
• The treatment plan depends on how the symptoms can best be organized into categories relating what is identified during physical examination