Drug Use and Misuse in the Mountains: A UIAA MedCom Consensus Guide for Medical Professionals

At altitude

The theoretical benefit of the glass of red wine before or during the ascent to ameliorate physical performance may be related to the inhibition of release of the potent pulmonary artery vasoconstrictor, endothelin-1 (ET-1), and increased generation of reactive oxygen species (superoxide anion, O₂−) by wine polyphenols, especially resveratrol, whose total content is greater in red wines than in white, rose, and distilled spirits. The ingestion of one glass (100 mL) of standard dry red wine (∼12% alcohol) provides 12 grams of ethanol. This low-dose ethanol may inhibit increased vasoconstricting ET-1 synthesis and superoxide anion generation in response to altitude hypoxia. The effect of red wine may be both through ethanol itself and by many of the polyphenols such as resveratrol that it also contains. Especially red wine is a rich source of polyphenols and their ability to enhance endothelial-type nitric oxide (NO) synthase (eNOS) expression in humans has been demonstrated (Wallerath et al., 2005).

Low concentrations of alcohol induce increased release of NO from the human endothelial cells due to activation of eNOS, which exerts important effects in physiological blood flow and blood pressure, with vasoprotective effects preventing pathological vascular damage (Toda and Ayajiki, 2010). Perhaps this explains the preference of some mountain climbers for that glass of red wine that makes them feel better (Schafer and Bauersachs, 2002).

The effects of excessive intake of alcohol may be exacerbated by other altitude-related factors such as dehydration, sleep disorders, fatigue, and cold and, in turn, its diuretic effect may worsen dehydration. Alcohol has marked effects on judgment and decision-making. It also reduces reflex times, interferes with balance motor control and coordination, and also impairs the ability to assess and manage risk. Its slow degradation means that the effects persist well beyond a traditional alpine start: also small amounts of blood alcohol concentration of 0.03 g/L can persist for a substantial period of time after the acute effects of alcohol impairment disappear (Roeggla et al., 1995).

Doping

Alcohol (ethanol) is only prohibited in-competition in some sports (e.g., air sports, archery, automobile, karate, motorcycling, and powerboating). Detection is conducted by blood or breath gas analysis. The doping violation threshold is 0.10 g/L on blood samples (WADA, 2016b).

Conclusions

The American College of Sports Medicine concludes that acute alcohol consumption adversely affects psychomotor skills and exercise performance depending on dose, age, and metabolic activity (American Heart Association Nutrition Committee et al., 2006). Ethanol may slow postexercise recovery by inhibiting protein synthesis and increases the risk of injury during exercise by reducing decision-making capability, reflex times, and balance (Barnes et al., 2010a; Pesta et al., 2013; Haugvad et al., 2014). A possible theoretical beneficial effect of moderate consumption of red wine at altitude is that it may help to prevent or ameliorate symptoms of high altitude pulmonary edema (HAPE) by inhibition of ET-1synthesis (Fellermeier et al., 2001).

Recommendations

Excessive intake of alcohol should be avoided before and during medium- to high-grade exercise in mountains as it will exacerbate fitness debilitating factors (e.g., dehydration, hypothermia), reduce exercise performance, delay recovery, and increase the risk of injury. Recommendation Grade: 1A.

Use in sport

Anabolic–androgenic steroids can benefit athletic performance. Short-term administration can increase strength and body weight, attributed to an increase of the lean body mass. Although anabolic–androgenic steroid administration may affect erythropoiesis and hemoglobin concentration, no effect on endurance performance was observed (Anonymous, 1990; Urhausen et al., 2003; Powers, 2005). The serious adverse effects of anabolic–androgenic steroids are dependant on dose, duration of use, and individual genetic factors (Friedl, 2000; Hartgens and Kuipers, 2004; Wilson, 2008; Luijkx et al., 2013).

At altitude

The psychological side effects reported by studies include sleeplessness, increased irritability, depression, change in mental attitude, psychotic symptoms, and feelings of euphoria and grandiosity (Tabin and McIntosh, 2001) and these can have fatal consequences. No governing body monitors recreational climbers for drug use, although anabolic–androgenic steroids have been and are being used in the preparation of expeditions and hard rock climbs. Several famous rock climbers admit to using anabolic–androgenic steroids to speed their recovery from injury or to improve performance (Tabin and McIntosh, 2001).

Doping

Anabolic–androgenic steroids are banned by virtually every sporting organization. The WADA includes all anabolic–androgenic steroids and precursors and all hormones and related substances at all times, both in- and out-competition (WADA, 2016b).

Conclusions

The multiple adverse effects seen at sea level may be even more pronounced at altitude and interfere with the diagnosis of high altitude cerebral edema (HACE). Their use is contraindicated.

Recommendations

Anabolic–androgenic steroids should not be used at any time by any mountaineer. Recommendation Grade: 1B.

Inhaled β₂-agonists and sport

A review performed by Kindermann in 2006 on the use of inhaled β ₂ -agonists (studies using Salmeterol, Formoterol, Orterbutaline, and Salbutamol) in nonasthmatic competitive athletes revealed that there are no performance-enhancing effects and no ergogenic potential of these agents in normoxia (Kindermann and Meyer, 2006). No data exist about possible ergogenic effects in hypoxia. A number of factors can induce an acute asthmatic attack in predisposed athletes, including exposure to pollen, dust, chemical particles, viral infections, and psychological stress (Pierson et al., 1986; Helenius et al., 1998). Physical exercise may give rise to specific exercise-induced asthma (Tikkanen and Helenius, 1994).

Inhalation of large volumes of cold dry air with resultant bronchial edema adds to the problem, so athletes participating in winter sports are at increased risk (Heir and Oseid, 1994). Currently, all β₂-agonists are prohibited by WADA in- and out-competition, with the exception of Formoterol, Salbutamol, Salmeterol, and Terbutaline when inhaled to prevent and treat asthma and exercise-induced asthma. Some β₂-agonists (i.e., Salmeterol and Salbutamol) have received interest in the prevention and treatment of HAPE due to their ability to enhance alveolar clearing of the fluid.

At altitude

Clinical experience with Salmeterol at high altitude is limited. In one randomized placebo-controlled study, the inhaled long-acting β₂-adrenergic agonist, Salmeterol, at 2.5 times the normal dosing decreased the incidence of HAPE by 50% in susceptible individuals (Sartori et al., 2002; Luks et al., 2014). The theoretical benefit proposed by Sartori et al. (2002) occurs through changes in pulmonary transepithelial sodium transport. The tightening of the alveolo-capillary barrier, the direct lowering of pulmonary artery pressure, the indirect hypoxic ventilatory stimulation, and increased NO production may also explain the beneficial effects in the reduction in the incidence of HAPE (Vivona et al., 2001; Bartsch and Mairbaurl, 2002; Basnyat, 2002). Although this finding requires confirmation, this agent is considered useful and convenient in the prevention of HAPE and, by extension possibly, for treatment as well (Hackett and Roach, 2001; Sartori et al., 2002; Dunin-Bell and Boyle, 2009).

Wilderness Medical Society (WMS) Consensus Guidelines now suggest that Salmeterol used in high doses close to the toxic level may help in the prevention of HAPE in susceptible individuals if combined with Nifedipine (Luks et al., 2014). At high doses, the drug may present important side effects (headache, hypertension, tachycardia, muscular cramps, nasal congestion, tremor) (Hackett and Roach, 2001) and it remains unclear whether its possible benefits outweigh the risks compared with Nifedipine alone.

Doping

Salmeterol is not prohibited by the antidoping WADA Code when taken by inhalation in accordance with the manufacturers’ recommended therapeutic regime (WADA, 2016b).

Conclusions

Salmeterol can be used as a second-line therapy in the prevention of HAPE. With no scientific evidence, some mountaineers have assumed that Salmeterol may also increase physical performance, but evidence of improved performance is lacking (Carlsen et al., 1997; Sue-Chu et al., 1999).

At altitude

Salbutamol has not been studied for the prevention or treatment of HAPE. Only anecdotal experiences in the Himalayas using Salbutamol inhalers or nebulizers for the treatment of patients with HAPE indicate an increase in the pulse oximeter reading after administration of the drug (Basnyat, 2002). As Salbutamol should function similarly to Salmeterol, this agent could be considered for the prevention and treatment of HAPE (Hackett and Roach, 2001)

Debilitating dry cough is a frequent problem in subjects traveling to high altitude. Bakewell et al. (1999) showed that inhaled Salbutamol twice daily may prevent high altitude cough.

Doping

Salbutamol is not prohibited by the antidoping WADA Code. When taken by inhalation in accordance with the manufacturers’ recommended therapeutic regime (maximum 1600 μg over 24 hours) (Berges et al., 2000; Nichols, 2004), overall performance is not improved (Koch et al., 2015).

Conclusions

Because of contradictory results and limited experience at altitude, its use is not recommended by UIAA MedCom.

At altitude

No studies have been performed at altitude for acute mountain sickness (AMS) prevention or treatment.

Doping

Clenbuterol is included by WADA in the prohibited list of performance-enhancing drugs, banned in- and out-competition (WADA, 2016b).

Conclusion

Its use at altitude or in any aspect of mountaineering is not recommended.

Recommendations

In general, the use of inhaled β₂-agonists in nonasthmatic mountaineers is not recommended. Salmeterol at the dose of 125 μg twice/day could be used for HAPE prevention or treatment, but only in conjunction with other medications. Recommendation Grade: 2B.

β-Blockers and sport

Bradycardia and the negative inotropic effects are of special importance when these drugs are used in sport since these changes decrease the myocardial oxygen demand (Tesch, 1985). Exercise-induced β-adrenergic stimulation leads to β-mediated coronary vasodilation. Thus, during exercise, the heart pumps faster and more forcefully, while the coronary flow is increased. Conversely, β-blockade should have a coronary vasoconstrictive effect with a rise in coronary vascular resistance. However, the longer diastolic filling time, resulting from the decreased heart rate in exercise, leads to better diastolic myocardial perfusion to give an overall positive benefit (Tesch, 1985).

Bronchospasm occurs in susceptible individuals due to blockade of β₂-receptors, which mediate dilation in the bronchi. Asthma is a contraindication for β-blockers (American Pharmacists Association, 2012). Peripheral vasoconstriction may result in cold hands and feet due to reduced cardiac output and possibly blockade of β₂-receptors, which promote vasodilation in blood vessels supplying skeletal muscles. Tiredness and fatigue may be due to reduced cardiac output exacerbated by blockade of β₂-receptors in skeletal muscle and associated with increased muscle activity (American Pharmacists Association, 2012).

At altitude

The high prevalence of hypertension in the general population means that it is also common among skiers, hikers, and visitors to moderate and high altitude. β-blockers are used for blood pressure regulation because they decrease sympathetic activity, but the frequency of therapeutic β-blocker use in mountaineers is unknown (Bouissou et al., 1989; Berg et al., 2004; Tissot van Patot et al., 2005; Luks, 2009; Dehnert and Bartsch, 2010; American Pharmacists Association, 2012). As expected, β-blockers limit the cardiac response to hypoxia, but do not impair the ventilatory response and do not modify the susceptibility to high-altitude-related illness (Richalet et al., 2013). Regular β-blocker intake in hypertensive elderly persons can provoke oxygen desaturation during submaximal exercise, leading to reduced exercise tolerance in people taking β-blockers at acute high altitude (Faulhaber et al., 2003).

In a study performed to evaluate the effects of different β-blockers (selective and nonselective) on cardiopulmonary response to exercise at high altitude, Valentini et al. (2012) found that Nebivolol may be preferred due to better preserved peak oxygen consumption (VO₂), increased peak minute ventilation, and peripheral vasodilation. β-Blockers may induce bronchospasm in susceptible individuals with exercise and cold air-induced asthma (Van Wijck et al., 2012). β-Blockers may interfere with thermoregulation in response to heat or cold (Mieske et al., 2010). β-Blockers are contraindicated in individuals with Raynaud's phenomenon (American Pharmacists Association, 2012). Frostbite may be a risk at high altitude (Luks, 2009).

Doping

β-Blockers are prohibited in-competition in specific sports. In archery and shooting, they are also prohibited out-competition. Currently, β-blockers are accepted for competition climbing (WADA, 2016b).

Conclusions

β-Blockers may be helpful for blood pressure regulation at high altitude because of increased sympathetic activity, but they reduce the maximum pulse rate and therefore limit maximal workload in healthy subjects, and can decrease circulation to the extremities, potentially putting the person at a higher risk of frostbite. Patients with coronary heart disease may benefit by the use of β-blockers because the work of their myocardium will be optimized and the oxygen demand lowered. β-Blockers have been used to reduce the physical symptoms of stress and anxiety and consequently might be considered by sport climbers.

Recommendations

The use of β-blockers may be recommended for patients who are already established on chronic antihypertensive β-blocker medication. The use of β-blockers at high altitude limits the cardiac response to hypoxia, does not impair the respiratory response, and does not modify susceptibility to high-altitude-related illnesses. Recommendation Grade: 1B.

At altitude

Dehydration due to exertion, low humidity, vomiting, or diarrhea may be exaggerated in those taking diuretics. Electrolyte disturbances, particularly hypokalemia, can develop and predispose subjects to life-threatening consequences. Rehydration salts and dried fruit (especially apricots and bananas) may resolve the problem (West et al., 2012).

Doping

According to the WADA Prohibited List, diuretics belong to the group of masking agents. Drugs in this category are prohibited at all times (WADA, 2016b).

At altitude

Doping

Acetazolamide is listed by WADA because it can camouflage doping tests, but not because it has any effect on performance (WADA, 2016b).

Conclusions

Acetazolamide is currently the gold standard if drugs must be used for the prevention of AMS and probably HACE (Severinghaus, 2001; Luks et al., 2014). Acetazolamide does not protect against worsening AMS with continued ascent (Luks et al., 2014).

Recommendations

US boxed warning

ESAs increase the risk of serious cardiovascular events, stroke, thromboembolic events, mortality, and tumor progression when administered to target hemoglobin levels >12 g/dL (American Pharmacists Association, 2012).

At altitude

Drugs such as EPO, ESAs, or other erythropoietic products aim to stimulate erythropoiesis at altitude. It should be stressed that all low oxygen states, including hypoxia of high altitude, cause physiological EPO release. By increasing oxygen-carrying capacity, EPO increases aerobic capacity and performance in endurance sports, including mountaineering, but at higher risk of thrombosis due to dehydration (Tabin and McIntosh, 2001). Other studies using simulated altitude conditions and oxygen deprivation (e.g., acute exposure to 12.6% O₂) have shown that ESA treatment causes hemoglobin and accordingly arterial oxygen content to increase both in normoxia and hypoxia, but at maximal exercise in hypoxia, maximal oxygen uptake (VO₂max) is not increased (Lundby and Damsgaard, 2006).

Prolonged administration of recombinant human EPO increases submaximal performance more than maximal aerobic capacity (Thomsen et al., 2007). A study performed at Annapurna base camp (4130 m) (Heo et al., 2014) showed that epoetin α pretreatment decreased AMS incidence in those requiring immediate descent with no adverse effects. The fact that EPO or ESAs have contradictory effects on performance illustrates that their use is based on theory rather than medical evidence. This increase of red blood cells and thickening of blood come with the risk of serious cardiovascular events, stroke, and other thromboembolic events. High altitude exposure initially causes rapid plasma and extracellular volume losses, while erythrocyte volume is unaffected, thus viscosity increases. Diluting blood to reduce viscosity with a plasma volume expander administrated simultaneously with EPO will probably increase exercise capabilities more than augmenting the total red cell volume alone (Sawka et al., 2000). In reality, this increased viscosity of blood results in reduced cardiac output and in less oxygen-carrying capacity in the blood (Young et al., 1996).

Doping

Blood doping is defined as the use of illicit erythropoietic products (EPO, ESAs, peginesatide, hypoxia-inducible factor stabilizers) and increasing aerobic capacity methods (blood transfusions, blood substitutes as hemoglobin-based oxygen carriers, and perfluorocarbons) used to maximize the uptake of O₂ and to enhance O₂ transport to the muscles, thus improving athlete's aerobic capacity (VO₂ max) and endurance (Robach et al., 2008). According to the WADA Prohibited List, all these products and methods are prohibited at all times (WADA, 2016b).

Conclusions

EPO and ESAs aim to increase erythropoiesis and by this VO₂max, resulting in little improvement in athletic performance. The side effects may be very dangerous at high altitude. Combining the unpredictable effects of EPO on each climber's individual physiology associated with the possibility of dehydration, malnourishment, and altitude sickness (all possible events when living at high altitude) makes EPO use risky for mountaineers.

Recommendations

Avoid the use of EPO. It is better to rely on sophisticated changes in blood, with natural acclimatization that has evolved over millions of years. Recommendation Grade: 1C.

Generic name: Dexamethasone

Dexamethasone is a synthetic steroid medication (Blue and Lombardo, 1999) with a variety of therapeutic actions. It suppresses inflammation by stimulating neutrophil migration, reversing capillary permeability, and decreasing production of inflammatory mediators and it acts as an immunosuppressant agent. It may be used in management of cerebral edema associated with brain tumor. Unlicensed use includes prevention and treatment of AMS and HACE (Ferrazzini et al., 1987; American Pharmacists Association, 2012).

Corticosteroids represent one of the most important drug classes for prevention and treatment of AMS and their benefits include their anti-inflammatory and antiedema effects. More recently, it has been speculated that corticosteroids may protect against increase in vascular endothelial and blood–brain barrier permeability, suppress inflammatory cytokines, reduce ROS formation upregulating endogenous antioxidant enzyme synthesis, and with a potent sympatholytic action for suppression of adrenergic tone (Swenson, 2016)

Patients receiving Dexamethasone report moderate–severe problems with insomnia (45%), indigestion and epigastric discomfort (27%), agitation (27%), increased appetite (19%), weight gain (16%), and acne (15%). Side effects encompassing cardiocirculatory function, lungs, gastrointestinal system, skin, and hair are also reported (American Pharmacists Association, 2012).

At least 853 drugs are known to interact with Dexamethasone. For instance, if combined with Acetylsalicylic acid, it increases its antiplatelet effects increasing the risk of internal bleeding from stomach and gut, brain, retina, and respiratory system. Dexamethasone should be taken with meals to decrease gastrointestinal upset. Salt in the diet should be reduced to avoid fluid retention. Ethanol or Acetylsalicylic acid, which may enhance gastric mucosal irritation, should be avoided (American Pharmacists Association, 2012).

At altitude

Doping

The WADA prohibits all glucocorticosteroids used in-competition whether administered by oral, intravenous, intramuscular, or rectal routes (WADA, 2016b). Athletes who are prescribed glucocorticoids may take these medications out-competition without submitting a therapeutic use exemption (TUE) as long as the prohibited substance has cleared their system before the time defined as in-competition. If athletes need to use these drugs shortly before or during competition, they must obtain a TUE. Inhalation of glucocorticoids (e.g., for asthma) is permitted. Injections of glucocorticoids around tendons, into joints, and epidural (into the spine) are permitted, but an injection into a muscle is prohibited.

Conclusions

The use of corticosteroids has to be a personal decision for mountaineers. These agents can cause significant side effects and the risk/benefit equation is very different from that for Acetazolamide (Basnyat, 2002). Dexamethasone should be available on any high altitude expedition for treatment of HACE and HAPE to buy time for rapid descent or when the descent is impossible (Levine et al., 1989; O'Hara et al., 2014). It can be lifesaving and use in short courses for emergency treatment will avoid many of the potential long-term side effects.

Recommendations

Oxygen at high altitude

Although the percentage of oxygen in inspired air is constant at different altitudes, the fall in atmospheric pressure with ascent decreases the partial pressure of inspired oxygen and hence the driving pressure for gas exchange in the lungs. The weight of air above us is responsible for the atmospheric pressure, which is about 760 mmHg (101 kPa) at sea level, and as oxygen is 20.9% of dry air, the inspired oxygen pressure is 149.6 mmHg (20 kPa) (Peacock, 1998). Atmospheric pressure and inspired oxygen pressure fall with altitude to be 50% of the sea level value at 5500 m and only 30% of the sea level value at 8848 m (summit of Mt. Everest) (Peacock, 1998). The first line of O₂ transport from the environment to the blood is the ventilatory air convection. West (1982, 1990b) has pointed out that this function is the most important adaptive parameter during ascent to high altitude and that it allows some acclimatized humans to reach the top of Mt. Everest.

Hyperventilation is one of the most important features of acclimatization to high altitude. Resting ventilation at extreme altitudes increases up to fourfold and exercise ventilation for a given work level increases to the same extent. Hypoxic stimulation of peripheral chemoreceptors is the chief mechanism for hyperventilation, but there is also evidence that central sensitization of the respiratory centers occurs. Cardiac output increases in responses to acute hypoxia, but returns to normal in acclimatized lowlanders. Oxygen uptake at extreme altitudes is markedly limited by the diffusion properties of the blood–gas barrier. As a consequence, the maximal oxygen consumption of a climber near the summit of Mt. Everest is near his basal oxygen requirements. Maximal oxygen consumption is so sensitive to barometric pressure that it may be that seasonal or day-to-day variations will affect the chances of a climber reaching the summit without supplementary oxygen (West, 1999; West et al., 2012).

Oxygen transport by red blood cells is regulated by erythropoiesis and Hb-O₂ affinity. The O₂-carrying capacity is characterized by changes in hematocrit, red blood cell count, or the mass of circulating red blood cells. Erythropoiesis is controlled by the hormone, EPO, which induces slow changes of the O₂ transport capacity. The Hb-O₂ affinity is modified mainly by pH and 2,3-DPG. In hypoxia at high altitude, despite their apparently diverse effects, a compromise seems to be adopted, optimizing both arterial O₂ loading and peripheral O₂ unloading. In contrast to erythropoiesis, adjustments of Hb-O₂ affinity occur quickly and allow rapid adjustments of O₂ binding and release. In severe hypoxia, adjustments of both, hematocrit and Hb-O₂ affinity, are insufficient to maintain tissue O₂ supply (Lenfant et al., 1968; Mairbaurl, 1994).

Delivery systems

Providing supplemental oxygen in adverse conditions at 8000 m is not simple. Frozen valves, deformed masks, ice formation in the tubing, and other problems can prevent the delivery of the right amount of oxygen at the right time. Too much and there is waste of gas, too little and the climber may die. Modern, light reliable systems are now available (Windsor et al., 2005, 2008).

Supplemental oxygen and mountaineering

Doping

No formal competitions take place at extreme altitude, so WADA has made no judgment on oxygen use.

Conclusions

It is for the individual climber to make their own ethical and tactical decisions. Supplemental oxygen should be available on climbing expeditions to 8000-m peaks for optimal treatment of HACE and HAPE. Supplemental oxygen is recommended for rescues at high altitude (>6500 m). Medically, UIAA Medcom recommends the use of supplementary oxygen on peaks above 7500 m. Being active mountaineers, the UIAA Medcom members do admire those mountaineers with the experience, skill, fitness, and physiology to climb safely above this altitude without supplementary oxygen while being aware of the risks involved.

Recommendations

Supplemental oxygen should be available on climbing expeditions to 8000-m peaks for optimal treatment of HACE and HAPE. Recommendation Grade: 1A.

Supplemental oxygen should be provided in rescues at high altitude (>6000 m). Recommendation Grade: 1A.

Theophylline–Acetazolamide (see also respective chapters)

Insomnia at altitude is associated with increased waking and periodic breathing or apnea due to effect of hypoxemia and poor acclimatization. Acetazolamide has been shown to have beneficial effects on sleep disturbances (Wickramasinghe and Anholm, 1999; Rodway et al., 2011; Windsor and Rodway, 2012; Richalet, 2013). A randomized, double-blind placebo-controlled study was conducted to evaluate the effects of both Theophylline and Acetazolamide in the treatment of SDB after fast ascent to high altitude (3454 m), showing that both drugs are effective in normalizing high-altitude sleep disorders.

Both Theophylline (250 mg × 2 daily) and Acetazolamide (250 mg × 2 daily) reduced oxyhemoglobin desaturation during sleep, with a reduction in obstructive events during sleep compared with the incidence of central apnea of controls (Küpper et al., 2008b). Acetazolamide also significantly improved basal oxyhemoglobin saturation during sleep compared with Theophylline (86.2% vs. 81%) (Fischer et al., 2004). In addition to the established side effects of Acetazolamide, if taken at night, its diuretic effect can interrupt sleep.

Recommendations

Theophylline and Acetazolamide should be considered for reducing the occurrence and intensity of sleeping disorders. Recommendation Grade: 1B.

Hypnotics

Insufficient data exist to determine which agent is most effective at altitude, nor is it known whether combination therapy with Acetazolamide and a hypnotic agent offers any benefits over monotherapy (Luks, 2008).

Generic name: Loprazolam

Some studies demonstrated that benzodiazepines improve sleep quality and do not aggravate periodic breathing (Duff and Gormly, 2012; Richalet, 2013). Goldenberg et al. (1988, 1992) showed that Loprazolam (1 mg) did not worsen either slow-wave sleep (SWS) depression or apnea and allowed normal sleep reappearance after acclimatization. On the contrary, other limited evidence suggests that it may cause hypoventilation at high altitude (Roggla et al., 1994). Benzodiazepines with a long half-life such as diazepam risk cause accumulative impairment of reasoning.

Benzodiazepine use in this environment should be discouraged especially when combined with alcohol.

Generic name: Temazepam

Temazepam, a short-acting benzodiazepine, has been shown to improve sleep quality, but to only cause a small decrease in mean oxygenation in unacclimatized climbers (Dubowitz, 1998).

The addition of Theophylline or Aminophylline has been shown to reduce the sedative effects of Temazepam and other benzodiazepines (Katzunget al., 2012).

At altitude

During a Himalayan expedition, both Acetazolamide (250 mg × 2) and Temazepam (10 mg) were used between 4100 and 4846 m. Compared with placebo (only Acetazolamide 250 mg × 2), there were no prolonged sleep latencies, less wakefulness and drowsy sleep, and increased sleep duration in the first 6 hours after ingestion (290 and 231 minutes, respectively), and sleep quality evaluated by visual analog scale was at sea level values (Nicholson et al., 1987).

In a randomized, blinded, crossover placebo-controlled trial at base camp of Mt. Everest (5300 m), participants taking Temazepam (10 mg) showed no significant drop in mean oxygen saturation during sleep. The quality of sleep improved as a result of a reduction in the number of awakenings, a greater respiratory stability, and fewer episodes of periodic breathings (Dubowitz, 1998). In another double-blind, randomized crossover trial at 5000 m, Temazepam (10 mg) was effective in reducing periodic breathing, safe to use, and without any adverse effect on next-day performance (Nickol et al., 2006).

Short-acting benzodiazepine Temazepam (10 mg) given with Acetazolamide (500 mg slow release) improved sleep and maintained SaO₂%, counteracting a 20% decrease in SaO₂% when Temazepam was given alone (Manang, Nepal, at 3540 m) (Bledsoe et al., 2009).

Last, the first comparative, randomized double-blind trial of Temazepam (7.5 mg) versus Acetazolamide (125 mg) taken at bedtime for one night at an altitude of 3540 m showed no difference with regard to mean nocturnal oxygen saturation, proportion of the night spent in periodic breathing, relative desaturations, sleep onset latency, awakenings, wake after sleep onset, sleep efficiency, daytime drowsiness, or change in self-reported Lake Louise Score. The Acetazolamide group reported significantly more awakenings to urinate (Tanner et al., 2013).

Conclusions

Benzodiazepines are controversial. As a general rule, the use of drugs such as Diazepam should be discouraged as they decrease the respiratory drive causing hypoventilation, especially if combined with alcohol. Studies would suggest that Temazepam may have a useful role in management of altitude insomnia.

Recommendations

Benzodiazepines should not be used at high altitude. Alcohol will increase benzodiazepine-related adverse effects, for example, nocturnal hypoventilation and desaturation and day sedation. Recommendation Grade: 2B.

Between 4000 and 5000 m, coingestion of Acetazolamide (500 mg) and Temazepam (10 mg) may result in a sleep quality comparable with sea level values. Recommendation Grade: 1B.

Temazepam (10 mg) taken up to 5300 m may improve sleep quality by reducing awakening and providing a greater respiratory stability and fewer episodes of periodic breathing, without any negative side effects during night or detrimental effects on next day's performance. Recommendation Grade: 1A.

Generic names: Zolpidem, Zaleplon

The new-generation hypnotic drugs, Zolpidem and Zaleplon, are at least as efficacious as benzodiazepines and may offer advantages in terms of safety due to their very short half-life. Frequency of side effects may be dosage and age dependent, and include headache, somnolence, dizziness, hypertension, rash and urticaria, and arthralgia (Muller et al., 1987; American Pharmacists Association, 2012).

At altitude

Zolpidem improved sleep characteristics at 4000 m, inducing a decrease in sleep onset latency (placebo, 22 ± 12 minutes vs. Zolpidem, 10 ± 6 minutes), an increase in SWS (stage three of non-rapid-eye-movement [non-REM] sleep) duration (placebo, 46 ± 28 minutes vs. Zolpidem, 69 ± 28 minutes), and a reduction in the arousal index during SWS (placebo, 7.4 ± 4.1/h vs. Zolpidem: 2.4 ± 1.0/h) (Beaumont et al., 1996).

A 2007 double-blind, randomized, placebo-controlled crossover trial at 3613 m to assess the effects of Zolpidem and Zaleplon on nocturnal sleep as well as on daytime attention, fatigue, and sleepiness showed no adverse effect on nighttime SpO₂, daytime attention levels, alertness, or mood (Beaumont et al., 1996, 2007; Jouanin et al., 2009).

Conclusions

Hypnotic nonbenzodiazepine drugs treat both physiological and environmental causes and seem to work without affecting respiratory drive, so sleep quality and structure were improved. With no studies describing the effects of high doses of hypnotic drugs at altitude, common sense and experience suggest high doses are inadvisable and should definitely be avoided if AMS is identified (Luks, 2008).

Recommendations

Up to 3600–5000 m, Temazepam (7.5–10 mg at bedtime), Zolpidem (10 mg), and Zaleplon (10 mg) are often taken for night rest without proven effects on ventilation, attention, or performance, but great care should be exercised in their use when combined with an early alpine start for an ascent. Recommendation Grade: 1A.

Hypnotic nonbenzodiazepines should be avoided in AMS. Recommendation Grade: 1B.

Generic name: Amphetamines

Amphetamines act primarily by enhancing the brain activity of noradrenaline and dopamine, intensifying psychological sensations of alertness, concentration, and self-confidence (Sulzer et al., 2005; Cruickshank and Dyer, 2009). Amphetamines are indicated for the treatment of attention-deficit–hyperactivity disorder and narcolepsy. The effects of amphetamine include an increase in physical energy, mental aptitude, talkativeness, restlessness, excitement, and good humor. Subjects taking amphetamine also report that they feel confident, efficient, ambitious, and that their food intake is reduced (Heal et al., 2013). Some negative effects of amphetamine (that can be dose dependent) are anxiety, indifference, slow reasoning, irresponsible behavior, irritability, dry mouth, tremors, insomnia, and, following withdrawal, depression (Heal et al., 2013). The role of sympathomimetic drugs in the pulmonary arterial pressure response to hypoxia is well known. Amphetamines may lead to pulmonary artery hypertension due to the release of synaptic dopamine, norepinephrine, and serotonin, which may cause pulmonary vasoconstriction, enhancing the risk of HAPE at altitude (van Wolferen et al., 2005).

Generic name: Cocaine

Cocaine is an extract from the leaves of the coca bush (Erythroxylum coca) native to South America (Biondich and Joslin, 2015). Coca tea has often been recommended for travelers in the Andes. Cocaine is the most potent stimulant of natural origin (Casikar et al., 2010). Cocaine modifies the action of dopamine in the brain and this increased activation of the dopaminergic reward pathway leads to a feeling of euphoria (Barnett et al., 1981; Kuhar, 1992). Physical effects of cocaine use include constricted blood vessels, dilated pupils, and increased temperature, heart rate, and blood pressure. It also increases motor activity (Cone et al., 1998). Complications associated with cocaine use include disturbances in heart rhythm and heart attacks (risk of cardiac sudden death increased more than 20-fold), chest pain and respiratory failure, strokes, seizures, headaches, and gastrointestinal complications (abdominal pain and nausea). Cocaine misuse is strongly associated with cerebrovascular accidents arising either from rupture or spasm of cerebral blood vessels (Barnett et al., 1981; Pomara et al., 2012).

Generic name: Cannabinoids

Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. The most notable cannabinoid is the tetrahydrocannabinol, the primary psychoactive compound of cannabis (Fellermeier et al., 2001). The dried leaves and flowers of the cannabis plant are known as marihuana, which can be smoked or taken orally with food (baked in cookies). The resinous secretions of the plant are known as hashish, which can be smoked or eaten.

Generic name: Mescaline

Mescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class, known for its hallucinogenic effects similar to those of Lysergic acid diethylamide (LSD) and psilocybin. It shares strong structural similarities with the catecholamine, dopamine (Nichols, 2004). Users typically experience visual hallucinations and radically altered states of consciousness, often experienced as pleasurable and illuminating, but occasionally with feelings of anxiety or revulsion. Other effects include open- and closed-eye visualizations, euphoria, dream-like state, laughter, and a psychedelic experience (Monte et al., 1997). Side effects of mescaline use may include anxiety, tachycardia, dizziness, diarrhea, vomiting, and headache (Monte et al., 1997).

Stimulants at altitude

Stimulant drugs have a long story in the mountains. Anecdotal accounts suggest that many ascents of 8000-m peaks in the 1950s were done with the use of amphetamines (Pervitin = methylamphetamine). A 1993 study in the Austrian Alps found amphetamines in the urine of 7.1% of mountaineers going above 3300 m (Roggla et al., 1993). WADA has reported international top class competition climbers testing positive for both amphetamines and cocaine (Boghosian et al., 2011). At high altitude, central effects of stimulants such as perceptual misjudgments and time disorientation may cause life-threatening risks for a mountaineer (Roggla et al., 1993). Coca-derived products are commonly recommended for prophylaxis for travelers in the Andes, and anecdotal reports suggest they are now also being used by trekkers in Asia and Africa. Their use in prevention of AMS has never been systematically studied, and they should not be substituted for other established preventive measures (Luks et al., 2014). Only one small study suggests that chewing coca leaves may be beneficial during exercise and that the effects are felt over a prolonged period of sustained physical activity (Braiden et al., 1994).

Stimulants and doping

A total of 62 stimulants (from 61 chemical entities) are listed in the WADA list. Many of these compounds are old agents, with research going back to the 1950s and 1960s, long before modern techniques and knowledge of receptor subtypes were studied in detail (Boghosian et al., 2011; WADA, 2016b). All stimulants are prohibited, except substances included in the 2016 Monitoring Program (caffeine, nicotine, etc.). Due to the transient advantage they give in nature, stimulants are prohibited in-competition only; this means that an athlete who is not competing does not need to obtain a TUE to use these drugs (WADA, 2016b).

Conclusions

The risk of overexertion is high when using stimulants. This may result in exhaustion, hypothermia, collapse, and death. Euphoric effects of stimulants may lead to poor decision-making, resulting in mountain accidents.

Recommendations

Stimulants should not be used during mountaineering as they reduce attention and may increase the chances of risk-taking and exhaustion. Recommendation Grade: 1B.

Benefits for acclimatization are unproven. Recommendation Grade: 1C.

Generic name: Acetylsalicylic acid

Acetylsalicylic acid irreversibly inhibits cyclooxygenase-1 and -2 (COX-1 and -2) enzymes, through acetylation, which results in decreased formation of prostaglandin precursors; this inhibits formation of prostaglandin derivate, thromboxane A₂, through acetylation of platelet COX, thus inhibiting platelet aggregation (Vane and Botting, 2003). Many adverse effects are dose related and dependent on patient susceptibility. Extensive side effects encompassing cardio-circulatory function, lungs, gastrointestinal system (6%–31%), skin, and hair are reported (American Pharmacists Association, 2012).

At altitude

Burtscher showed the efficacy of Acetylsalicylic acid as prophylaxis against headache when mostly resting during acute high-altitude exposure (320 mg Acetylsalicylic acid, one tablet every 4 hours, starting 1 hour before arrival at 3480 m altitude and then after 3 and 7 hours after arrival) (Burtscher et al., 1998). Acetylsalicylic acid probably prevented high altitude headache since acute hypoxia augments prostaglandin concentration and prostaglandins increase. In a second study (Burtscher et al., 2001) using the same drug protocol, Acetylsalicylic acid reduced the incidence of headache when exercising during acute altitude exposure: climbers were transported to an altitude of 3000 m and then climbed up to 3800 m. Afterward, they descended to a mountain hut at 3480 m and spent two nights there. Its antiplatelet effect increases the risk of internal bleeding, which could be further increased if combined with Dexamethasone (i.e., gastrointestinal bleeding) (Vane and Botting, 2003; Wu and Liu, 2006; Wu et al., 2007). The potential benefit in reducing clotting at high altitude to prevent the risk of venous thrombosis is negligible (Stovitz and Johnson, 2003).

Generic name: Ibuprofen

Ibuprofen reversibly inhibits COX-1 and −2 enzymes, which results in decreased formation of prostaglandin precursors (American Pharmacists Association, 2012).

At altitude

Two prospective, double-blind placebo-controlled studies (Gertsch et al., 2012; Lipman et al., 2012) have evaluated the use of Ibuprofen for prevention of AMS. The authors of both studies cite the importance of inflammation in the pathophysiology of AMS (Olesen, 1994; Tissot van Patot et al., 2005; Julian et al., 2011) as supporting evidence that a nonsteroidal anti-inflammatory drug should be of benefit in preventing AMS. As the authors point out, this favors the conclusion that Ibuprofen acts to prevent the constellation of symptoms rather than just treating the headache. Another study comparing Acetaminophen (i.e., acetaminophen 1000 mg) with Ibuprofen (400 mg) for the prevention of AMS might shed light on the relative importance of antiheadache and anti-inflammatory effects because Acetaminophen has no significant anti-inflammatory effect, but is effective against headache (Harris et al., 2003).

Ibuprofen does carry potentially serious risks such as gastrointestinal hemorrhage (Van Wijck et al., 2012), but tends to have fewer overall side effects than Acetazolamide. Unlike Dexamethasone, it does not cause euphoria or decrease nausea. Its analgesic and antiheadache properties are limited and unlikely to mask significant symptoms (Broome et al., 1994). The fact that it is widely available without a prescription makes it an attractive option for prevention of AMS. Current evidence suggests that Ibuprofen is effective in the prevention of AMS and that its benefit is not limited to preventing headache. It is likely that ibuprofen acts by decreasing inflammatory responses to hypoxia (Zafren, 2012). Ibuprofen is used to mask soft tissue pain in endurance mountain marathon runners and sport climbers (Stovitz and Johnson, 2003; Nieman et al., 2006), but it aggravates exercise-induced small intestinal injury in 20% of healthy endurance athletes (Van Wijck et al., 2012).

Generic name: Sumatriptan

Selective agonist of serotonin (5-HT_1B and 5-HT_1D receptors) in cerebral arteries, Sumatriptan, causes vasoconstriction and reduces neurogenic inflammation associated with antidromic neuronal transmission correlating with relief of migraine (American Pharmacists Association, 2012).

At altitude

Three reports suggest the efficacy of Sumatriptan for the treatment of high altitude headache (Bartsch et al., 1994; Utiger et al., 2002; Jafarian et al., 2007b). A randomized, placebo-controlled double-blind trial performed at 4559 m on 29 mountaineers, receiving 100 mg orally, noted a significant decrease of headache scores one and 3 hours after administration, but not after 12 hours, concluding its possible use only for a transient amelioration of headache (Utiger et al., 2002). Jafarian et al. conducted a prospective, double-blind, randomized, placebo-controlled clinical trial, in 102 subjects at 3500 m within 24 hours of ascent. Sumatriptan 50 mg was effective to prevent AMS development (Jafarian et al., 2007b). In nine subjects at 4559 m, 100 mg of Sumatriptan reduced the headache score from mean 2.8 to 0.8 (p < 0.01, Wilcoxon signed rank test) (Bartsch et al., 1994).

Burtscher et al. (1995), in a randomized double-blind trial (33 subjects at 3480 m, Sumatriptan 100 mg or Ibuprofen 600 mg), showed that Ibuprofen, but not Sumatriptan, was effective for high-altitude headache (nearly complete relief in the Ibuprofen group, no decrease of the score in the other group).

Generic name: Gabapentin

Gabapentin is structurally related to gamma-Aminobutyric acid (GABA). Gabapentin modulates the action of glutamate decarboxylase and branched-chain aminotransferase, two enzymes involved in GABA biosynthesis. In human and rat studies, Gabapentin was found to increase GABA biosynthesis and to increase nonsynaptic GABA neurotransmission in vitro (Petrucci et al., 2016).

At altitude

Two studies were performed at 3500 m to evaluate the treatment of Gabapentin on altitude headache (Jafarian et al., 2007a, 2008). The first was on 12 subjects at an altitude of 3500 m receiving 300 mg of Gabapentin and 12 placebos. Nine subjects of the placebo group asked for additional analgesia. The mean headache-free period in the Gabapentin group was 17.1 hours, significantly longer than in the placebo group (10.1 hours). The second study was on 204 unacclimatized subjects aged 15–65 years, at the same altitude, assigned randomly to 600 mg single dose of Gabapentin or placebo. The incidence of headache was the same, but the severity of headache was lower in the Gabapentin group with acceptable tolerability. The drug's side effect profile would put most climbers off using it (including dizziness, somnolence, fatigue, and paresthesia) (American Pharmacists Association, 2012)

Doping

The four mentioned analgesics are not included in the WADA list of prohibited agents.

Conclusions

There are several ways to prevent AMS when going to high altitude. The most reliable and safest method is gradual ascent to allow time for acclimatization. In an extensive evidence based medicine (EBM) review from 2000 to 2011 (Seupaul et al., 2012), different studies have reported reduction in the incidence of AMS with the use of Gabapentin or Sumatriptan and have showed that Ibuprofen is effective in the prevention of AMS and not limited to preventing headache. It is likely that the primary effect of Acetylsalicylic acid may simply be on headache control rather than true prevention of AMS. A greater beneficial effect may be achieved by the combined application of Acetazolamide and Acetylsalicylic acid (Basnyat et al., 2008a). This combination increases oxygenation and reduces prostaglandin synthesis, but the adverse effects of Acetylsalicylic acid should not be underestimated.

Recommendations

Acetylsalicylic acid (320 mg every 4 hours for a total of three doses) or Ibuprofen (400 or 600 mg once, may be repeated) may be used in the prevention and in the treatment of high altitude AMS-related headache. Recommendation Grade: 1A.

Side effects of nonopioid analgesics should be considered (e.g., internal bleeding). Gastrointestinal bleeding risks are higher when combined with Dexamethasone or simply when at high altitude. Recommendation Grade: 1B.

Gabapentin (300 mg) and Sumatriptan (50–100 mg before ascent) may help prevent AMS, Recommendation Grade: 2B.

Generic name: Morphine

Morphine binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain, and producing generalized CNS depression (Busch-Dienstfertig and Stein, 2010; American Pharmacists Association, 2012).

Generic name: Codeine

Codeine or 3-methylmorphine is a naturally occurring methylated morphine, with the same mechanism of action (Busch-Dienstfertig and Stein, 2010).

Generic name: Tramadol

Tramadol and its active metabolite (M1) bind to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain. It also inhibits the reuptake of norepinephrine and serotonin, which also modifies the ascending pain pathway (American Pharmacists Association, 2012).

At altitude

Opioids should be avoided during acute altitude exposure or illness due to their respiratory depressant effects (Teichtahl and Wang, 2007). Respiratory side effects are exacerbated with alcohol, sedatives, sleeping pills, sedating antihistamines, or prochlorperazine (Gudin et al., 2013). Tramadol has a less depressant effect on respiration than the other opioids (Rojas-Corrales et al., 1998). The theoretical possibility of developing HAPE as a result of a hypoxic increased pulmonary capillary hydrostatic pressure and an increased pulmonary capillary permeability due to hypoxemia, potent histamine release, and respiratory acidosis caused by depression of medullary respiratory centers must be taken in account (Radke et al., 2014). There is no HAPE recorded in FDA reports in 38,699 people who have side effects while taking Tramadol (eHealthMe, 2016).

Central sleep apnea is induced by the use of opioids. In 2007, a study conducted at an elevation of 1500 m showed a dose-dependent relationship between chronic opioid use and the development of specific central sleep apnea and ataxic breathing (Gudin et al., 2013). Constipation is a common side effect of opioids, so a laxative must be given if more than a few doses are taken. Only consider opioids for abdominal pain if constipation has been excluded and the victim is moving his bowels normally due to the risk for paralytic ileus (Dubowitz, 1998; Duff and Gormly, 2012). In a 1969 comparison, Carson showed that codeine 132 mg was less efficacious than a placebo in the prevention of AMS (Dumont et al., 2000). Opioids should be used with extreme caution in patients with head injury (American Pharmacists Association, 2012).

High altitude dry cough is associated with inflamed mucous membranes in the respiratory tract. Codeine-containing preparations may be of some limited value as a cough suppressant (Duff and Gormly, 2012).

Doping

All opioids are included in the list of WADA substances and methods prohibited in-competition (WADA, 2016b).

Conclusions

At altitude >2500 m, any medication that depresses respiration may make AMS, HACE, and HAPE more likely or worse. Most reviews conclude that opioids produce impairment of human performance on tests of sensory, motor, or attention abilities and can bring excessive risks, with very little advantage. The only ethical medical use is for treatment of severe pain (Tramadol 50 mg tablets one–two every 4 hours, up to maximum 400 mg/24 h or Codeine 30 mg one–two tablets every 4 hours as needed) (Duff and Gormly, 2012).

Note

Opioids are illegal in many countries, even in transit. Carry appropriate Customs forms. Check country requirements with relevant government departments.

Recommendations

Opioids should not be used for exertional purposes. Recommendation Grade: 1B.

Opioids should be considered in the treatment of severe pain. Recommendation Grade: 1A.

Generic name: Nifedipine

Nifedipine is a dihydropyridine calcium channel blocker (CCB) that primarily blocks L-type calcium channels. It works by affecting the movement of calcium into the cells of the heart and blood vessels. Nifedipine inhibits the spasm of the coronary artery and dilates the systemic arteries, resulting in increase of myocardial oxygen supply reducing its workload. The vasodilatory effects of Nifedipine result in an overall decrease in blood pressure. It is also used for the small subset of pulmonary hypertension patients whose symptoms respond to CCBs. Headache (10%–23%), peripheral edema (7%–30%), dizziness (10%–27%), flushing (10%–25%), nausea, and heartburn (10%) are the most important side effects. Symptoms of overdose include dizziness, drowsiness, nausea, severe drop in blood pressure, slurred speech, and weakness.

The rapid reduction in blood pressure may precipitate adverse cardiovascular events and peripheral edema may lead to an increased risk of frostbite. Alcohol may increase CNS depression and may increase the effects of Nifedipine. Natural licorice and grapefruit in all forms (e.g., whole fruit, juice, or rind) can significantly increase levels of Nifedipine, may cause toxicity, and should be avoided (Kulhmann et al., 1986; Ramsch et al., 1986; American Pharmacists Association, 2012).

At altitude

Nifedipine effectively lowers hypoxic pulmonary hypertension and improves gas exchange in patients with HAPE. These result in regression of alveolar and interstitial edema (Simonneau et al., 1981). For its arterial pulmonary vasodilatory effect, Nifedipine is cheap, effective, lifesaving, and the drug of choice in the treatment of HAPE (Oelz et al., 1989, 1991, 1992; Luks and Swenson, 2008; Maggiorini, 2010; Luks et al., 2014). In mountaineers with HAPE at 4559 m, treatment with 20 mg slow-release Nifedipine taken every 6 hours led to a persistent relief of symptoms, improvement of gas exchange, and radiographic clearance over an observational period of 34 hours. In this study, Nifedipine therapy was not associated with hypotension (Maggiorini, 2006).

Being effective in the treatment of increased pulmonary artery pressure during acute high altitude exposure, Nifedipine may have a role in the prevention of HAPE in susceptible individuals (Bartsch et al., 1991). Twenty milligrams of Nifedipine of the slow-release formulation taken every 8 hours starting 24 hours before ascent to 4559 m and continued until descent decreased the incidence of HAPE from 63% to 10% (Maggiorini, 2006).

If symptoms are present despite Nifedipine prevention, prophylaxis with Acetazolamide is recommended (Greene et al., 1981; Basnyat et al., 2003). Whether Acetazolamide prophylaxis prevents HAPE is yet unknown, although Acetazolamide inhibited hypoxic pulmonary vasoconstriction in animals (Berg et al., 2004; Hohne et al., 2004), but failed to do the same in a large study of partially acclimatized humans in the Everest region (Basnyat et al., 2008b).

Nifedipine does not treat or prevent AMS. Many studies demonstrated that lowering pulmonary artery pressure has no beneficial effects on gas exchange and symptoms of AMS (Hohenhaus et al., 1994; Maggiorini et al., 2006). Its use in high altitude medicine should be limited to prevention and treatment of HAPE and, if used for prevention, it cannot then be used for treatment (Hohenhaus et al., 1994). For treatment, first check that the patient is not already on hypertension therapy with a CCB. Marked hypotension may be precipitated if used in very dehydrated patients or those receiving other antihypertensive drugs (phosphodiesterases [PDE]-5I, β-blockers, α-blockers, other CCBs) (Donegani et al., 2014). At altitude, slow-release preparations should be preferably used. If the patient is semiconscious, but swallowing, the Nifedipine capsule (10 mg) may be pierced and the liquid squirted into his mouth (use with caution); blood pressure lowering should be done at a rate appropriate for the patient's conditions (Luks and Swenson, 2008). Note: Although often stated to the contrary, the patient must be able to swallow, otherwise the drug will have no effect (van Harten et al., 1987).

Note

Management of pulmonary hypertension, prevention and treatment of HAPE, is an off-license use (Kulhmann et al., 1986; American Pharmacists Association, 2012).

Doping

Nifedipine is not included in the WADA prohibited list.

Conclusions

Nifedipine can be used specifically for treatment of severe HAPE to buy time for vital lifesaving descent. In specific cases, it may be used for prevention to minimize the risk of HAPE developing.

Generic name: Sildenafil, Tadalafil

Both Sildenafil and Tadalafil are not only primarily used to treat erectile dysfunction but are also effective in the treatment of pulmonary arterial hypertension. They relax the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure (Jeon et al., 2005; Kirsch et al., 2008; Sakuma and Shirato, 2008; Wang et al., 2012). Side effects include headache (16%–46%), epistaxis (9%–13%), dyspepsia (7%–17%), flushing (10%), insomnia (7%), myalgia (7%), exacerbated dyspnea (7%), abnormal vision (color changes, blurred vision, or increased sensitivity to light) (3%–11%), diarrhea (3–9%), and erythema (6%) (American Pharmacists Association, 2012). In the same trial, several participants reported feeling subjectively more fatigued and unable to mentally focus during exercise while on active drug treatment (Hsu et al., 2006). Blood pressure may drop due to vasodilator effects (Cheitlin et al., 1999; Chrysant, 2013). Concurrent use with alpha-adrenergic antagonist therapy or substantial alcohol consumption may cause symptomatic hypotension. Avoid concomitant use with organic nitrate vasodilators and be careful if combined with CCBs. Substantial consumption of ethanol may increase the risk of hypotension and grapefruit may increase serum levels to toxic levels (American Pharmacists Association, 2012).

At altitude

A limited number of studies have evaluated the use of the PDE5-I as preventive/therapeutic agents for mountain sickness (Kleinsasser and Loeckinger, 2002; Maggiorini et al., 2006; Fagenholz et al., 2007; Jouanin et al., 2009). PDE5-I is not effective in preventing AMS (Maggiorini, 2006; Jouanin et al., 2009). In some susceptible individuals, PDE5-I may possibly exacerbate AMS by an unknown mechanism (Ghofrani et al., 2004).

Prevention of HAPE

Prevention of HAPE in individuals with a positive history of HAPE could be obtained using 10 mg Tadalafil bid: the incidence of HAPE was 74% in the placebo and 10% in the Tadalafil group (randomized placebo-controlled trial, at 4559 m, eight subjects, p < 0.007 vs. placebo) (Maggiorini et al., 2006). The number of individuals in the study was small and extensive clinical experience with the medication is lacking when compared with Nifedipine. Regardless, in the WMS guidelines for the prevention and treatment of altitude illness, Sildenafil and Tadalafil, with longer half-life, are recommended only for HAPE prevention (Luks et al., 2014).

Treatment of HAPE

By virtue of their ability to cause pulmonary vasodilation and decrease pulmonary artery pressure, there is a strong rationale for using PDE5-Is in HAPE treatment (Kirsch et al., 2008; Jin et al., 2010), but to date there are no clinical trials on the use of more selective pulmonary vasodilators such as Sildenafil or other phosphodiesterase-5 inhibitors for HAPE treatment (Maggiorini, 2006). In one small study (Fagenholz et al., 2007), 11 patients were treated for HAPE at 4240 m in Nepal using concomitant drugs (Nifedipine and Acetazolamide in all, Sildenafil in most).

Altitude-induced hypoxia can cause severe decrements in submaximal and maximal exercise performance. These decrements can be attributed, in part, to a ventilation–perfusion mismatch. Strategies to reduce pulmonary hypertension in hypoxia would be predicted to improve oxygen diffusion and arterial oxygen saturation (SaO₂), cardiac output, and exercise performance (Salisbury and Hawley, 2011). Richalet et al. (2005) and Faoro et al. (2007) observed an increase of exercise SaO₂ after 3 days of treatment. Bates et al. (2011) showed a trend toward higher SaO₂ at day 1, but any difference between treatment and control groups for up to 7 days. On the contrary, Xu et al. (2014) showed that short-term treatment attenuated the pulmonary systolic arterial pressure, but had no significant beneficial effects on SaO₂, heart rate, and AMS. Other studies have investigated the effects of PDE5-I on exercise performance at altitude (Zhao et al., 2001; Ghofrani et al., 2004; Aldashev et al., 2005; Perimenis, 2005; Ricart et al., 2005; Richalet et al., 2005; Hsu et al., 2006; Reichenberger et al., 2007) and these studies showed that certain individuals can benefit from Sildenafil use during acute hypoxia, but not normoxia, in terms of cardiac output, arterial saturation, and exercise performance (Di Luigi et al., 2008).

Doping

Sildenafil and Tadalafil (PDE5-I) are not included in WADA prohibited list.

Conclusions

Currently, limited data and experience at altitude with side effects could be potentially dangerous at altitude. PDE5-Is should be used with caution at altitude.

Recommendations

Generic name: Caffeine

Caffeine is a psychoactive drug whose stimulant properties depend on its ability to block adenosine transmission in the brain. Caffeine has vasoconstriction properties, antagonizing adenosine receptors in the blood vessels and reducing adenosine-mediated vasodilatation, thereby decreasing cerebral blood flow, myocardial blood flow, and exercise-induced myocardial flow reserve (Namdar et al., 2006; Umemura et al., 2006). Caffeine stimulates ventilation, increasing hypoxic ventilatory response, hypercapnic ventilatory response, and thus ventilatory response to exercise. Additionally, caffeine increases resting ventilation and metabolic rate (Fisone et al., 2004; Lorino et al., 2006; Chapman and Stager, 2008; American Pharmacists Association, 2012).

Caffeine can improve exercise performance at low altitudes (An et al., 2014; Fernandez-Elias et al., 2015; Diaz-Laraet al., 2016; Richardson and Clarke, 2016). The mechanism is both central with reduced perceived exertion and peripheral with increased muscular force from changes in calcium utilization, stimulating the release of calcium ions from the sarcoplasmic reticulum (Graham, 2001; Paluska, 2003; Burke, 2008; Woolf et al., 2008; Davis and Green, 2009; Goldstein et al., 2010). Side effects include palpitations, sinus and supraventricular tachycardia, arrhythmias, angina, and flushing; agitation, dizziness, delirium, hallucinations, insomnia, irritability, restlessness, and psychosis; urticaria; esophageal sphincter tone decreased, gastritis; fasciculations; and intraocular pressure increase, miosis. Diuresis is increased (American Pharmacists Association, 2012; WADA, 2016b).

Typical caffeine contents of commonly consumed beverages (Hackett, 2010) are as follows: instant coffee (8oz [1oz = 30 mL] cup) 40–110 mg, coffee espresso (2oz cup) 100 mg, black tea (8oz cup) 50 mg, green tea (8oz cup) 30 mg, Coca Cola (12oz can) 34 mg, Pepsi Cola (12oz can) 38 mg, and Red Bull (8oz can) 80 mg.

Caffeine and theine are chemically identical; the only thing that sets them apart is the concentration, lesser in a cup of tea than in a cup of coffee. Tea is the most widely consumed beverage in the world after water. Tea is known to be a rich source of caffeine, flavonoid antioxidants (oxidized polyphenols), and also contains a unique amino acid, L-theanine, which may modulate aspects of brain function in humans. One randomized, placebo-controlled, double-blind, balanced crossover study investigated the acute cognitive and mood effects of L-theanine (250 mg) and caffeine (150 mg), in isolation and in combination. The results suggest that beverages containing L-theanine and caffeine show a significant positive interaction and may have more pronounced cognitive effects to those containing caffeine alone (faster simple reaction time, faster numeric working memory reaction time, and improved sentence verification accuracy) (Haskell et al., 2008).

In addition, other data indicate that L-theanine has a significant positive effect on the general state of mental alertness or arousal (Scott et al., 2004; Bryan, 2008; Nobre et al., 2008; Camfield et al., 2014).

At altitude

Because of its capacity to reduce cerebral vasodilation in response to hypoxia owing to its vasoconstriction properties, caffeine will help prevent or treat altitude headaches and therefore AMS. In addition, at high altitude, it may improve sleep by reducing episodes of oxygen desaturation. Caffeine reduces cerebral blood flow and the ratio of cerebral blood flow to cerebral metabolic rate for oxygen. Caffeine stimulates ventilation and this effect could be more pronounced where ventilation is already markedly increased and therefore at high altitude this may be helpful. Studies of caffeine and exercise are limited, but they suggest that caffeine might confer more benefit to performance at high altitude than at sea level and do not suggest that it might impair exercise.

Caffeine does have diuretic effects, but with normal consumption, even in an environment of cold and altitude where diuresis is stimulated, caffeine did not increase diuresis with no risk for dehydration (Hackett, 2010). A study performed by Scott et al. (2004) showed that there is no evidence that tea acts as a diuretic when drunk by regular tea drinkers at altitude, but it does have a positive effect on mood. It also did not increase the altitude-induced increase of heart rate significantly.

Caffeine may interfere with sleep and promotes wakefulness, so it is recommended avoiding caffeine in the late afternoon or evening, especially in nonhabitual users, to avoid caffeine-induced insomnia, which could aggravate altitude-associated insomnia (Hackett, 2010). Habitual caffeine users should not discontinue it because of travel to altitude since withdrawal symptoms are very similar to those of AMS (Hackett, 2010).

Doping

Caffeine was removed from the WADA Prohibited List in January 2004 since it is present in a wide range of popular foods, metabolized at very different rates in individuals with different urinary concentrations, which do not always correlate with the dose ingested. In 2012, following concerns raised by some sport physiologists, WADA included caffeine in the 2012 Monitoring Program to monitor potential misuse in sport, keeping the situation under review (WADA, 2016b).

Conclusions

Even at physiological doses (3–6 mg/kg), caffeine provides an ergogenic aid especially in endurance events. It has a peripheral effect targeting muscle metabolism as well as a central effect on the brain to enhance performance, which is also relevant for anaerobic performance. Postexercise caffeine intake seems to benefit recovery by increasing rates of glycogen resynthesis.

Recommendations

Caffeine (1.5–3 mg/kg) may help exercise performance at altitude. Recommendation Grade: 1B.

Generic name: Theophylline

Theophylline is a drug used for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. As a xanthine, it bears structural and pharmacological similarity to caffeine and theobromine (Scott et al., 2004). Theophylline is naturally found in cocoa beans. Trace amounts are also found in brewed tea. Theophylline causes bronchodilation, diuresis, CNS and cardiac stimulation, and increased gastric acid secretion (Schultze-Werninghaus and Meier-Sydow, 1982; Essayan, 2001). The metabolic effect of theophylline was studied (Greer et al., 2000), demonstrating that this substance is ergogenic independent of muscle glycogen (Pigozzi et al., 2003). Adverse effects observed at therapeutic serum levels include tachycardia and flutter, hyperactivity, insomnia, restlessness, seizures, tremor, hypocalcemia (with concomitant hyperthyroidism), nausea, vomiting, gastric reflux, difficulty urinating (elderly males with prostatism), and increased diuresis (American Pharmacists Association, 2012).

At altitude

Theophylline at low dose (300 mg daily) is known to significantly reduce AMS symptoms at altitude (Küpper et al., 2008b). The mechanism found for the beneficial effect is most likely related to stimulation of respiratory drive reducing the frequency of oxygen desaturation during sleep (Fischer et al., 2004; Küpper et al., 2008b). Additional effects of theophylline on AMS symptoms may include a decrease in adenosine-mediated cerebral blood flow or a reduction in inflammatory responses and vascular permeability as a result of its phosphodiesterase inhibitor activity. There is also no evidence that theophylline increases significantly the heart rate at altitude (Küpper et al., 2008b).

If combined with dehydration, alcohol, smoking, or even viral illness, even a low dose of Theophylline (250 mg slow release) can lead to potentially dangerous toxicity (Fischer et al., 2000), although such problems were never observed at altitude so far (Fischer et al., 2004; Küpper et al., 2008b). This drug has multiple interactions with other drugs and a narrow therapeutic range. With Acetazolamide, Theophylline can decrease the potassium level in blood and if combined with Azithromycin, which is often used to treat traveler's diarrhea, it can easily reach toxic levels (American Pharmacists Association, 2012).

Doping

Theophylline has been discussed at WADA since 2003, but it is not prohibited, although it increases performance at sea level (WADA, 2016b).

Conclusions

Theophylline could be considered an alternative to reduce AMS symptoms in those intolerant of Acetazolamide, but it has potential side effects, many drug interactions, and a narrow therapeutic range.

Recommendations

Low-dose slow-release theophylline (300 mg) may be used to reduce symptoms of AMS in association with alleviation of events of periodic breathing and oxygen desaturations. Recommendation Grade: 1B.

At altitude

No data available.

Doping

Since January 1, 2016, Meldonium has been on the WADA list of substances banned from use by athletes. WADA classes the drug as a metabolic modulator, just as it does insulin (WADA, 2016b). However, there are debates over its use as an athletic performance enhancer. Some athletes are known to have been using it before its ban. In March 2016, WADA made a partial retraction on Meldonium (WADA, 2016a). WADA admitted that there are only limited data on how quickly the drug is cleared from the human body. It was found that low levels of the drug could show up in an athlete's urine for a few months, meaning some positives could have been the result of the athlete using the drug before it was banned. Based on preliminary data and awaiting ongoing studies, WADA stated that if the urine level of the drug was <1 μg/mL, the result is compatible with an intake before January 2016, and the responsible antidoping agency could clear the athlete. Other levels were adjusted to allow for a potentially long washout period.

Conclusion

No data exist on whether this substance might be of benefit or harm or how it might work in hypoxia.

Recommendations

Meldonium should not be used at any time by any mountaineer. Recommendation Grade: Expert opinion.