Psychological pain interventions
The significant psychological strain that comes with chronic pain often receives too little attention. In patients with a chronic illness, the likelihood of developing mental impairments is increased twofold or threefold [25
], a fact that must be considered when dealing with hemophilia patients. Possible comorbidities include depressive episodes, anxiety disorders, and personality disorders. The extent of these illnesses is decisive when it comes to resources and deficits with respect to pain processing and coping.
Not all hemophilia patients who suffer from chronic pain require psychological intervention. Indications for such an intervention, however, are dysfunctional pain experience and behaviour, insufficient stress management, psychosocial conflicts, issues at work, compliance issues, substance abuse, or psychiatric comorbidities.
The goals of psychological interventions include the patient dealing with the chronic illness, defining realistic goals, reducing patterns of fear and avoidance, creating strategies for coping with pain and stress as well as developing adequate pain communication and problem-solving approaches. This helps improve compliance and quality of life.
The first steps before any psychological treatment include in-depth anamnesis and exploration, often followed by psychological diagnosis based on available standards of diagnostics [26
]. The next step would ideally be interdisciplinary therapy planning, something that is usually only possible in large institutes. Examples of possible psychological interventions include:
Modalities of physical medicine
As a component of multimodal pain management [27
], physical medicine and rehabilitation play an important role by functioning as complementary treatments for acute pain and by preventing and treating chronic hemophilic arthropathy and the pain this causes. In collaboration with other disciplines, physical medicine thus contributes to improving or maintaining functionality.
As part of the overall treatment of hemophilia, exercise therapy plays an important role because many patients suffer from deficits in several basic motor functions: strength (especially in the extremities and back muscles) [28
], coordination/balance/proprioception [31
], flexibility [33
], and endurance performance [30
Chronic hemophilic arthropathy is associated with pain, strength deficits, muscle atrophy, contractures with inhibited range of motion as well as impaired intermuscular and intramuscular coordination. Hemophilic arthropathy leads to joint instability and angular deformities and may finally result in joint ankyloses and disability [1
Consequently, multimodal exercise is recommended to improve coordination, flexibility, range of motion, strength, general functionality and general fitness [1
]. A main goal is improved joint stability. Central and peripheral pain-reducing mechanisms of exercise are being discussed [44
Resistance exercise in combination with coordination and endurance training can improve joint stability and reduce the risk of injury, falls and bleeding [1
]. Adequate and individually adapted resistance exercise improves control over maximum degree joint movement and can reduce synovial impingement with associated bleeding or synovitis, while also promoting good bone density and possibly reducing pain in cases of arthrosis [8
]. Aerobic exercise can reduce the risk of obesity and metabolic and cardiovascular diseases [43
Aquatic therapy is an important therapy option for patients with hemophilia since it seems to reduce pain more effectively than land-based exercise, at least in adult patients [45
]. Aquatic therapy also leads to oedema reduction and a reduction of muscle spasms. It helps maintain range of motion, while improving balance, coordination, strength, and posture [8
Since pain leads to a change in joint function and to impaired motion sequence as well as to reduced therapeutic and exercise success, adequate analgesic treatment is essential before engaging in physical activity [51
]. At the same time sufficient factor supply in line with recommendations and guidelines must be ensured [1
]. Exercise should be adapted to the patient’s needs, deficits, level of fitness and joint status. It should be prescribed accompanied and increased by musculoskeletal specialists with experience in hemophilia [1
Physical medicine also has a prophylactic potential. Functional disorders caused by inflammatory processes often precede structural changes in joints and thus increase the risk of joint bleeds [52
]. Different examination methods can be used in order to catch structural or functional changes in joints early on, the basis for this being regular (depending on age and symptoms) and in-depth physical examinations [53
]. The hemophilia joint health score can be used for a thorough musculoskeletal assessment that includes the systematic detection of structural and functional arthropathic changes [54
]. In so far as they are available, further examinations, such as surface electromyography (EMG) and gait analysis can be used in order to detect possible individual functional deficits, functional disorders of the muscles, inappropriate weightbearing, and impaired motion sequence [52
]. Diagnostic imaging procedures that are useful for detecting osteochondral defects and synovitis include magnetic resonance imaging (MRI, gold standard) in particular, as well as ultrasound [52
]. The joints that are most commonly affected by hemophilia can be screened for early arthropathic changes using ultrasound (e.g., HEAD-US protocol) [54
]. For optimal adaptation of exercise therapy to a patient it is important to measure their physical fitness, e.g., using a dynamometer or ergometer. By way of early diagnosis of impairments or deterioration, adequate treatment can be initiated early on, thereby avoiding or reducing joint damage and the associated pain.
For patients with limited access to exercise facilities, home training programmes that are adapted to the disease and made available through online videos are an option. Specialist approval that also ensures adequate factor therapy and, ideally, constant supervision by musculoskeletal specialists are important [56
Low-frequency electrotherapy: transcutaneous electrical nerve stimulation (TENS) is used as an analgesic option in case of acute haemarthrosis and chronic pain [49
]. Iontophoresis with local NSAIDs stimulates circulation, provides a trophic stimulus and has an anti-inflammatory and analgesic effect [49
]. Neuromuscular electrical stimulation (NEMS) can increase muscle thickness and strength, as was shown in studies on the biceps and quadriceps muscles [59
]. Diadynamic currents (CP according to Bernard) [39
], Trabert current or high voltages are also used for analgesic therapy in people with hemophilia.
Medium-frequency interferential current has an oedema and haematoma-absorbing and analgesic effect [49
When prescribing electrotherapy (just like with any other physical therapy option), general contraindications have to be taken into account. In children and adolescents, there is a relative contraindication in the area of the epiphyseal plate. Just like with any other measure that increases circulation, using it on areas with an active or potential tissue bleed must be preceded by ensuring appropriate factor protection since most modes of electrotherapy stimulate the circulation locally [61
In cases where heat generation should be avoided, pulsed ultrasound can be used [57
], although evidence is not very strong. The analgesic effect can be improved through phonophoresis, whereby a medical gel with anti-inflammatory and analgesic substances is applied. Ultrasound is particularly effective when it comes to resolving adhesions caused by inflammation and breaking up fibrosis and scar tissue. It positively affects tissue repair and inflammatory processes [51
Massage techniques can also be indicated for analgesic purposes in patients with hemophilia. Examples include lymphatic drainage (reduces swelling), classical massage (reduces muscle tone, mechanically loosens fibrosis in the connective tissue, prevents adhesions when used subacutely after muscle bleeds) or Terrier massage (indicated in cases of increased muscle tone and limited mobility) [49
]. For intense treatment, sufficient factor protection is important.
During acute phases, the RICE principle (R
levation) is frequently used to treat pain [1
]. In cases of acute joint and muscle bleeds, cryotherapy reduces pain and hypoxic damage, and improves ischemic tolerance in the affected area [63
]; however, due to possible negative effects on platelet function and clotting factor activity, the literature reflects some controversy in this area [64
]. Cooling is recommended for a maximum of 15–20 min at a minimum of 2‑h intervals. The ice should be wrapped in a dry cloth to avoid direct skin contact [1
Heat treatment for muscles increases circulation and leads to a reduction in muscle tone; however, heat treatment can lead to increased muscle spindle activity and can consequently lead to reflectory muscle tension after the treatment [51
]; factor protection is indicated.
Other treatment options
Relaxation techniques like biofeedback, Jacobson’s relaxation technique or mental training as well as proprioceptive neuromuscular facilitation (PNF) can lead to improved body awareness [49
Acupuncture can also be an effective way of treating chronic pain in hemophilia patients [7
], although available publications report about a limited number of patients.
Other good therapeutic options for pain reduction and improvement of functional parameters include laser and pulsed electromagnetic field (PEMF) therapy, which was demonstrated for children in two studies [65
Depending on the level of physical limitation, orthoses, assistive devices, and insoles may be indicated [8
Pharmacological pain therapy
Basics of pharmacological pain therapy
Central elements of successful pharmacological pain therapy include:
classification of the underlying pain mechanism (nociceptive, inflammatory, neuropathic or nociplastic pain)
assessment of polypharmacy
consideration of organ insufficiencies and contraindications
regular monitoring of therapeutic response and possible adverse effects
In the spirit of a multimodal process, pharmacological pain therapy should always combine a variety of substances in order to try to maximise the analgesic effect. Hemophilia patients are often insecure concerning the pain medication they are allowed to use. Consequently, patient education on contraindicated and suitable substances is of the utmost importance. It is also crucial to bear in mind not just the individual substances’ effects on coagulation but any effect an interaction of different substances might have.
When choosing suitable substances, it is important to evaluate the risk-benefit ratio. The therapy should not just focus on pain intensity but the underlying pain mechanisms:
Nociceptive pain is caused by a stimulation of peripheral nociceptors and transmission of the pain stimulus along sensitive nerve fibres. Pain in muscles, ligaments, or joints falls into this category. Nociceptive somatic pain is localised and after consideration of possible contraindications and restrictions on use, it is typically treated with nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase‑2 inhibitors (coxibs), dipyrone (metamizole), and paracetamol; this type of pain responds well to opioids, too. In cases of nociceptive visceral pain, dipyrone is a good option; opioids and co-analgesics are also used.
Neuropathic pain is caused by an irritation of the peripheral or central nervous system, which may be caused by, for instance, an infiltration or compression of neural structures [67
In cases of neuropathic pain anticonvulsant drugs and antidepressants, opioids as well as topical therapies, such as lidocaine and capsaicin have therapeutic significance [68
In order to avoid or minimise adverse effects, analgesic drugs should be used at the lowest possible dosage and for as short a time as possible, but certainly long enough to sufficiently treat the pain and avoid chronification. Since insufficient pain reduction may lead to patients resorting to over-the-counter (OTC) analgesics, regular therapy monitoring is necessary.
Topical analgesics for hemophilia patients
Indications for topical analgesics include musculoskeletal pain, ligament injuries, joint diseases, muscle pain syndrome, and various spine-related pains.
The analgesic effect of topical NSAIDs corresponds to about 50% of the effect reached via systemic administration and entails significantly fewer adverse effects. Clinical evidence for the effectiveness of topical NSAIDs is generally quite convincing, particularly when it comes to acute musculoskeletal pain syndromes [69
Dermal tolerability of topical NSAIDs is good, although topical ketoprofen can cause photoallergic reactions.
Most topical NSAIDs are available in gel form. In order to optimise percutaneous bioavailability, it is important to be generous in terms of both the amount of gel used and application area [70
Topical applications of lidocaine and capsaicin are suitable for local, external treatment of neuropathic pain.
Non-opioid analgesics can be combined in order to improve analgesic efficacy, for instance COX inhibitors with paracetamol (acetaminophen) or dipyrone (metamizole). Due to a possible potentiation of the risk of adverse effects, different COX inhibitors, however, should not be combined.
Nonsteroidal anti-inflammatory drugs and coxibs
Both NSAIDs and selective COX‑2 inhibitors (coxibs), target the cyclooxygenase enzyme and have analgesic, antipyretic, and anti-inflammatory effects [71
There are two isoenzymes: COX‑1 and COX‑2 [72
]. COX‑1 protects the stomach lining, regulates renal perfusion and induces platelet aggregation via the production of thromboxane A2 in thrombocytes. In inflammation or swelling the net analgesic effect of this drug class can be superior to that of opioids. This goes for, e.g., naproxen, ibuprofen, mefenamic acid, and diclofenac [73
]; however, significant adverse effects are possible.
Among this drug class, acetylsalicylic acid (ASA) causes the most problems; even in small doses (30–50 mg), ASA irreversibly blocks COX‑1 in platelets, thus negatively influencing coagulation [74
]. Consequently, ASA is thoroughly unsuited for treating pain in hemophilia patients. This also goes for combination preparations with ASA.
As they have an anti-inflammatory effect and pose a lower risk of gastrointestinal adverse effects COX‑2 inhibitors, such as celecoxib are better suited for pain therapy in hemophilia patients. Etoricoxib was investigated in patients older than 12 years (n
= 102) and proved to be effective, safe, and well-tolerated when administered to patients with arthropathy [75
]. Due to the well-known renal, cardiovascular, and gastrointestinal safety profile, coxibs as well as NSAIDs should only be prescribed in the lowest effective dosage and for as short a time as possible. In cases of an existing cardiovascular comorbidity the COX‑2 inhibition leads to an exponential risk of recurrent cardiovascular events [76
]. Severe cardiovascular underlying diseases and cardiac insufficiency are therefore to be regarded as contraindications for COX‑2 inhibitors.
When prescribing NSAIDs special attention should be paid to possible polypharmacy (Table 1
). Administering Angiotensin-converting enzyme (ACE) inhibitors alongside NSAIDs can reduce the antihypertensive effect of this substance class and potentiate the risk of renal failure. NSAIDs also increase the risk of bleeding (especially gastrointestinal bleeding) when anticoagulants, corticosteroids, and selective serotonin reuptake inhibitors (SSRIs) are administered simultaneously [78
]. The use of antidepressants, antipsychotics, anticonvulsant drugs, and opioids can cause a severe electrolyte imbalance like hyponatremia. Alternatively, non-opioid analgesics such as paracetamol and dipyrone (metamizole) are an option for treatment.
Summary of selected analgesics interactions
Increased bleeding risk (especially in the gastrointestinal tract)
In combination with ACE inhibitors risk of renal failure
Risk of renal failure
With antidepressants, anticonvulsants, antipsychotics and opioids
Increased electrolyte imbalance like hyponatremia
With 5‑HT3 antagonists (e.g. ondansetron or tropisetron)
Reduction of analgesic efficacy
Increased incidence of arrhythmia in patients with cardiac impairments
Reduced resorption (at least 2‑h intervals between doses)
Possible impairment of cognitive and gross motor skills
In many cases, paracetamol (acetaminophen) is currently used as first-line therapy for treating pain in hemophilia patients even though no randomised clinical trial data for hemophilia patients are available.
Paracetamol is indicated for mild to moderate levels of pain. It has an antipyretic but no anti-inflammatory effect, and shows some COX‑2 inhibition. The recommended dosage to be administered at any one time is 10–15 mg/kg body weight. When overdosed multiple times paracetamol has a hepatotoxic effect, and so the approved maximum individual dosage of 15 mg/kg body weight or maximum individual dosage of 1 g and maximum daily dosage of 4 g for people weighing >50 kg should never be exceeded [80
]. Overdosing can lead to liver failure. Paracetamol does not inhibit platelet aggregation. Due to the peripheral selective COX‑2 inhibition, prolonged paracetamol administration increases the cardiovascular risk. According to available studies, 1g of paracetamol inhibits COX-2 at a rate of about 83% [81
]. High doses and prolonged administration can also lead to an increased risk of renal and gastrointestinal complications [82
]. In cases of hepatic insufficiency, paracetamol is contraindicated.
When paracetamol is administered together with 5‑HT3 receptor antagonists, the analgesic effect can be reduced (Table 1
). Caution should be exercised in cases of alcohol abuse and in combination with CYP2E1-inducing drugs due to the resulting faster metabolisation, which can lead to an increase in hepatotoxicity. In such cases, the dosage of paracetamol must be reduced.
Compared to paracetamol, dipyrone (metamizole) has a relatively high analgesic potency and is especially useful for visceral pain and colic. It has an antipyretic effect and can therefore be used to treat feverish infections, replacing NSAIDs which are problematic when treating hemophilia patients.
Dipyrone has low interaction and adverse effect potential [83
]. Dipyrone-induced agranulocytosis is a rare adverse effect in Central Europe; however, when administered over longer periods of time, regular blood cell counts are indicated [85
]. Overdosing leads to relatively low renal, hepatic, and gastrointestinal toxicity.
The temporary platelet dysfunction caused by dipyrone (metamizole) has been known for a long time and its clinical relevance is a matter of discussion [84
]. Consequently, the use of dipyrone (metamizole) in cases of known platelet dysfunction cannot be advised. In case of hemophilia, factor deficiency is most relevant. Refusal of short-term dipyrone (metamizole) use for the treatment of headaches, colic, pain in the soft tissue or fever is not justifiable. In a postoperative setting and in case of severe trauma, factor substitution and balancing coagulation in hemophilia patients is paramount. If dipyrone (metamizole) is used in such situations, a risk-benefit evaluation is indicated. In cases of renal insufficiency, the dosage of dipyrone (metamizole) should be reduced.
In accordance with their analgesic potency, weak opioids (tramadol, nalbuphine) and strong opioids (fentanyl, buprenorphine, morphine, hydromorphone, oxycodone, piritramide) are available.
The use of opioids is always indicated in combination with non-opioids as basic medication. By combining two non-opioids with a different mode of action, e.g., a coxib plus dipyrone (metamizole), the analgesic effect is increased leading to a possible opioid reduction of up to 40% [88
If non-opioids fail to reach the desired analgesic effect or if pain intensity is high, it is indicated to complement the therapy as soon as possible with opioids during an acute phase. That is also important to avoid chronification mechanisms.
The opioids are first administered intravenously, fractionated and titrated, or in an immediate release form that is given orally. With chronic joint pain, limited mobility, and inappropriate weightbearing, constant analgesic medication using a non-opioid plus extended release opioids may be required.
One advantage of opioids when compared to non-opioid analgesics is the low organ toxicity. The paramount principle when using opioids is start low, go slow: due to initial adverse effects like fatigue and dizziness opioids should first be administered in low doses and an increase in dosage should only be considered while constantly monitoring effects and adverse effects. Other undesired effects when administering opioids during an acute phase can include cardiovascular depression, sedation and the risk of falling that comes with it, pruritus, spasms in the urogenital area/urinary retention, and respiratory depression. The danger of respiratory depression is particularly high when opioids are given intravenously and where either the initial dose was too high, or the dosage was increased too quickly [10
]. Antiemetic prophylaxis at the beginning as well as constant obstipation prophylaxis are to be considered obligatory during opioid therapy.
The choice of opioid depends on the pain category, the pain intensity, the pain character and rhythm, possible comorbidities or contraindications, and the receptors involved.
For tramadol a ceiling effect has been established, which can make switching to a stronger opioid necessary. Tramadol is considered a second-line analgesic. It can be used to treat nociceptive and neuropathic pain.
When treating strong nociceptive pain, μ‑opioid receptor agonists like hydromorphone, oxycodone, fentanyl, buprenorphine, and morphine are particularly suitable. Neuropathic pain can be treated using oxycodone, buprenorphine or morphine.
Tapentadol with its dual mechanism of action as an agonist of the μ‑opioid receptor and as a norepinephrine reuptake inhibitor (NRI) has also proven to be an efficient and safe analgesic option, in particular in the treatment of neuropathic pain [89
When using opioids, it is paramount to take hepatic and renal comorbidities into account (Table 2
). Tramadol, and less frequently, oxycodone and fentanyl, can cause a serotonin syndrome when combined with an existing therapy of monoamine oxidase inhibitors (MAO) inhibitors or SSRI, serotonin-noradrenalin-reuptake-inhibitor (SNRI), tricyclic antidepressants, mirtazapine or trazodone and triptans. 5‑HT3 antagonists in combination with tramadol reduce its analgesic efficacy.
Analgesics used in cases of hepatic and/or renal insufficiency [104
Is metabolised by enzymes in the liver into hepatotoxic N‑acetyl-p-benzoquinone imine and therefore contraindicated in case of liver damage
Longer intervals of 8–12 h
No dosage adjustment
50% dosage reduction
50% dosage reduction
CAUTION increased spasticity, dosage adjustment necessary
Dosage adjustment because of increased risk of urine retention
No dosage adjustment
150–600 mg (divided into 3 daily doses)
No dosage adjustment
25–150 mg (divided into 2 daily doses)
Longer dosage interval of 12 h necessary, maximum daily dose: 200 mg
Longer dosage interval of 12 h, maximum daily dose: 200 mg
50% dosage reduction
50% dosage reduction
No dosage adjustment
No dosage adjustment
No dosage adjustment
25% dosage reduction
Longer dosage interval
25–50% dosage reduction
Possible dosage reduction
No dosage adjustment
Adjuvants and co-analgesics
Antidepressants and anticonvulsants
As part of multimodal pain therapy, antidepressants generally play an important role in neuropathic pain treatment. Selective serotonin reuptake inhibitors (SSRI) such as citalopram, paroxetine, or escitalopram are to be used with caution in hemophilia patients as they can inhibit platelet aggregation and therefore increase the risk of bleeding. First-line therapy of neuropathic pain uses tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors (SNRI) that do not influence coagulation [8
]. Using antidepressants to treat nociceptive pain is inadvisable. In addition, the dosage must always be strictly adapted to kidney and liver function. In cases of psychological changes in teenage pain patients, consulting psychological or psychiatric expertise is recommended.
Anticonvulsants such as gabapentin and pregabalin constitute first-line medication for the treatment of neuropathic pain. Adverse effects in the CNS include sedation, nausea, vomiting, headaches, dizziness, ataxia, and impaired vision; dermatoses like leukocytopenia and thrombocytopenia.
Dosage of both gabapentin and pregabalin must be adapted to kidney function.
For the treatment of acute pain, cannabinoids are not a suitable option but can have hyperalgesic effect. As for the treatment of chronic pain, limited data are available, making an evaluation difficult at this stage. Cannabinoids, both the psychoactive tetrahydrocannabinol (THC) and cannabidiol (CBD) which does not have psychoactive effects, can be used to treat neuropathic pain if first and second-line therapeutics show insufficient results. Cannabinoids generally only show a moderate analgesic effect of 30% on average. They can, however, have a positive effect on sleep, mood, and coping [90
Glucocorticoids have an antiphlogistic, anti-edematous, and analgesic effect, whereby the analgesia is brought on exclusively by the antiphlogistic properties.
At the outset of the therapy a high enough dosage is crucial; later on, however, need and necessity should be constantly monitored and the dosage reduced as quickly as possible. Patients need to be monitored closely in case of comorbidities, such as diabetes, cardiovascular diseases, peptic ulcer, recurring infection or glaucoma [62
Hyaluronic acid, chondroitin sulphate, glucosamine
Cartilage tissue itself is not innervated. Consequently, the analgesic effects of hyaluronic acid, chondroitin sulphate, and glucosamine do not directly affect this tissue. Hyaluronic acid and its building blocks, chondroitin sulphate and glucosamine, can only ever be used to help rebuild worn, damaged, or lost cartilage. Intra-articular injections, however, should not be administered to hemophilia patients [91
Chondroitin sulphate can be used to treat arthrosis and is administered perorally. Studies and meta-analyses of the analgesic and function-enhancing effects of chondroitin sulphate reflect a conflicting data situation. Currently, there is no certain proof for a chondroprotective effect in arthrosis. A combination of orally administered chondroitin sulphate and glucosamine sulphate used to treat arthrosis of the knee has not produced better results than the placebo when it comes to pain symptoms and functionality [93
Glucosamine is attributed with analgesic and anti-inflammatory effects and to protect or build up cartilage. At this time, however, there is no clear proof of any chondroprotective effects that glucosamine might have when used to treat arthrosis. A meta-analysis of orally administered glucosamine and chondroitin for arthritis showed that while chondroitin eased pain and improved functionality, glucosamine only improved joint mobility [94
]. When used to treat osteoarthritis, glucosamine and chondroitin showed no reduction in pain or joint space narrowing compared to the placebo [95
Although there is mixed evidence regarding their efficacy, a number of herbal agents are eligible for pain therapy [96
]. According to a Cochrane review of arthrosis of the hip and knee, the use of plant-based medicines is neither recommended nor advised against [97
]. There is, however, a body of sufficiently good evidence for a number of phytopharmaceuticals such as rampion or devil’s claw (Harpagophytum procumbens
), willow bark extract, frankincense (Boswellia serrata
) or comfrey root/herb (Symphyti radix/herba
) and their analgesic/antiphlogistic effects for them to be rated as well-established use or at least traditional use. Their use allows for a reduction in conventional analgesics. Also, their tolerability is usually very good, which is probably a result of their multitarget effect [97
Generally, the possibility of side effects and interactions in phytotherapy should not be underestimated. Potential interactions of phytopharmaceuticals that affect blood coagulation have to be considered: garlic and gingko biloba can reduce platelet aggregation when taken at the same time as anticoagulants, ginseng can reduce the effect of anticoagulants [103