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Dihydrocodeine
Dihydrocodeine
Dihydrocodeine
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Dihydrocodeine
Clinical data
Other names6α-Hydrocodol[1]
AHFS/Drugs.comInternational Drug Names
Dependence
liability		High
Addiction
liability		High
Routes of
administration
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityBy mouth: 21% (range 12–34%)[3]
Metabolism
Mainly hepatic, through CYP3A4 and CYP2D6
Metabolites• Dihydromorphine
• Nordihydrocodeine
• Others (e.g., conjugates)
Elimination half-life4 hours[3]
Identifiers
  • 4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.303 Edit this at Wikidata
Chemical and physical data
FormulaC18H23NO3
Molar mass301.386 g·mol−1
3D model (JSmol)
  • O[C@@H]1[C@@H]2OC3=C(OC)C=CC4=C3[C@@]2([C@H]5CC1)CCN(C)[C@@H]5C4
  • InChI=1S/C18H23NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3,6,11-13,17,20H,4-5,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1 checkY
  • Key:RBOXVHNMENFORY-DNJOTXNNSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Dihydrocodeine is a semi-synthetic opioid analgesic prescribed for pain or severe dyspnea, or as an antitussive, either alone or compounded with paracetamol (acetaminophen) (as in co-dydramol) or aspirin. It was developed in Germany in 1908 and first marketed in 1911.[4]

Commonly available as tablets, solutions, elixirs, and other oral forms, dihydrocodeine is also available in some countries as an injectable solution for deep subcutaneous and intra-muscular administration. As with codeine, intravenous administration should be avoided, as it could result in anaphylaxis and life-threatening pulmonary edema. In the past, dihydrocodeine suppositories were used. Dihydrocodeine is available in suppository form on prescription. Dihydrocodeine is used as an alternative to codeine and similarly belongs to step 2 of the WHO analgesic ladder.[5]

It was first described in 1911 and approved for medical use in 1948.[6] Dihydrocodeine was developed during the search for more effective cough medication, especially to help reduce the spread of tuberculosis, pertussis, and pneumonia in the years from c.a. 1895 to 1915. It is similar in chemical structure to codeine.

Medical uses

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Approved indication for dihydrocodeine is the management of moderate to moderately severe pain as well as coughing and shortness of breath. As is the case with other drugs in this group, the antitussive dose tends to be less than the analgesic dose, and dihydrocodeine is a powerful cough suppressant like all other members of the immediate codeine family (see below) and their cousins hydrocodone, oxycodone and ethylmorphine, whole opium preparations, and the strong opioid hydromorphone.[7][8]

For use against pain, dihydrocodeine is usually formulated as tablets or capsules containing 15–16 mg or 30–32 mg with or without other active ingredients such as aspirin, paracetamol (acetaminophen), ibuprofen, or others.[9][10]

Controlled release dihydrocodeine is available for both pain and coughing, as indicated below, as waxy tablets containing 60 to 120 mg of the drug. Some formulations, intended for use against coughing and the like, have other active ingredients such as antihistamines, decongestants and others.[11] Other oral formulations, such as packets of effervescent powder, sublingual drops, elixirs and the like are also available in many locations.[12]

Injectable dihydrocodeine is most often given as a deep subcutaneous injection.[13] Dihydrocodeine appears to be superior to tramadol in treating pain.[5]

Side effects

[edit]

As with other opioids, tolerance and physical and psychological dependence develop with repeated dihydrocodeine use. All opioids can impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving or operating machinery if taken in large doses.[14][15]

Itching and flushing and other effects of blood vessel dilation are also common side-effects, due to histamine release in response to the drug using one or more types of receptors in the CNS or other responses elsewhere in the body.[16] First-generation antihistamines such as tripelennamine (Pyrabenzamine), clemastine (Tavist), hydroxyzine (Atarax), diphenhydramine (Benadryl), cyproheptadine (Periactin), brompheniramine (Dimetapp), chlorphenamine (Chlor-Trimeton), doxylamine (NyQuil) and phenyltoloxamine (Percogesic Original Formula) not only combat the histamine-driven side-effects, but are analgesic-sparing (potentiating) in various degrees.[17][18] The antihistamine promethazine (Phenergan) may also have a positive effect on hepatic metabolism of dihydrocodeine as it does with codeine. Higher doses of promethazine may interfere with most other opioids with the exception of the pethidine family (Demerol and the like) by this or other unknown mechanisms.[19]

As with all drugs, side-effects depend on the person taking the medication. They can range in severity from mild to extreme, from headaches to difficulty breathing.[20][21]

Constipation is the one side-effect of dihydrocodeine and almost all opioids which is near-universal.[22][23] It results from the slowing of peristalsis in the gut and is a reason dihydrocodeine, ethylmorphine, codeine, opium preparations, and morphine are used to stop diarrhoea and combat irritable bowel syndrome (IBS) in its diarrhoeal and cyclical forms as well as other conditions causing hypermotility or intestinal cramping.[24] Opium/opioid preparations are used often as a last resort where pain is severe and the bowels are organically loose. It is generally better to treat IBS with a non psycho-tropic opioid such as loperamide hydrochloride which stays contained in the bowel,[25] thereby not causing drowsy effects and allowing many people to work using machines etc. For IBS, hyoscine butylbromide (Buscopan in the UK) and mebeverine hydrochloride (Colofac) can be effective with or without an opium related compound.[25]

Pharmacology

[edit]

Dihydrocodeine exerts its analgesic action through affinity to predominantly μ-opioid receptor and to lesser extent to κ-opioid receptor and δ-opioid receptor. 30 mg of subcutaneous dihydrocodeine is equianalgesic to 10 mg of morphine.[5] Another source states that dihydrocodeine is twice as strong as codeine[26][5] and the metabolite dihydromorphine is likewise twice as strong as morphine.[5]

Dihydrocodeine (DHC) is O-demethylated into dihydromorphine (DHM) by CYP2D6 and N-demethylated into nordihydrocodeine (NDHC) by CYP3A4, summarily yielding nordihydromorphine (NDHM). Dihydrocodeine and its metabolites form 3- and 6-glucuronides. Due to the multidirectional metabolism, as opposed to tramadol and codeine, CYP2D6 activity probably does not influence DHC analgesia. The analgesia is likely achieved by the action of DHC itself, as well as DHC-6-G.[5] DHC appears not to differ between poor and extensive metabolizers in terms of its pain threshold and pupillary reaction effect in spite of major variation in DHM blood levels.[27]

DHC-6-G is half as potent as DHC. DHM and DHM-6-G display the highest affinity to μ-opioid receptors, being 70 times as potent as DHC, whereas other metabolites display lesser affinity. DHM-6-G has similar potency as DHM, while DHM-3-G is considerably weaker. Action on δ-opioid receptor is 5-50 weaker compared to μ with the exception of DHC-6-G being twice as strong as DHC. 6-glucuronides possess lesser affinity towards κ-opioid receptors, albeit the affinity of DHC is comparable to codeine, DHM and morphine.[5]

The primary compounds responsible for analgesia are DHC and DHC-6-G. Although some of the metabolites are far more potent, the concentration of NDHM and NDHM-6-G in urine were minimal, suggesting no significant role in pain relief.[28][5]

After oral absorption, the drug is absorbed relatively rapidly with mean peak concentration at 1.7 hours. The mean half-life is 4 hours. The mean bioavailability of orally administered drug is 21%. Metabolite concentrations are high in relation to the parent drug, suggesting extensive first-pass metabolism.[29] Dihydrocodeine tablets may possess an extended-release mechanism, lowering peak concentrations and increasing duration of action.[5]

Regulation

[edit]
Australia
In Australia, dihydrocodeine is a 'pharmacist only' Schedule 3 drug, only when indicated for cough suppression, and compounded with one or more other therapeutically active substances not exceeding 15 mg dihydrocodeine per dose.[30] Schedule 3 drugs, while still OTC, can only be dispensed after consultation with a pharmacist. It is a Schedule 4 (prescription only) drug when compounded with one or more other therapeutically active substances and not exceeding 100 mg dihydrocodeine per dose.[30] Any Dihydrocodeine preparation not falling within Schedules 3 or 4, including single ingredient dihydrocodeine preparations, are categorised as Schedule 8 (controlled drugs), which can only be dispensed in accordance with the stricter requirements of the state or territory in which they are prescribed (and which vary between states and territories).[30][31][32]
Hong Kong
In Hong Kong, dihydrocodeine is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. A pharmacist can dispense Dihydrocodeine when furnished with a doctors prescription. Anyone who supplies the substance without a prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption, without a licence from the Department of Health, is illegal and carries a $1,000,000 (HKD) fine or 7 years imprisonment.
Japan
In Japan, dihydrocodeine is available without a prescription; used in cough medicines such as New Bron Solution-ACE. Dihydrocodeine is used as an antitussive in many products as a Dextromethorphan alternative. Medicines in Japan which contain dihydrocodeine are coupled with caffeine to offset the sedative effects and discourage recreational use. Cough medicines containing dihydrocodeine are controlled similarly to dextromethorphan in the United States, in that its sale is strictly limited by purchase quantity and is restricted to persons 20 and older for purchase.
United Kingdom
In the United Kingdom, dihydrocodeine is a Class B drug; but, it is available over-the-counter in small amounts (less than 8 mg), when combined with paracetamol (see co-dydramol). Dihydrocodeine is listed in Schedule 5 of the Misuse of Drugs Regulations 2001 whereby it is exempt from prohibition on possession provided that it is in the form of a single preparation not being designed for injection and less than 100 mg (calculated as free base) or with a total concentration less than 2.5% (calculated as free base). Illegal possession of dihydrocodeine can result in up to 5 years in prison or an unlimited fine.
United States
In the US, pure dihydrocodeine is a DEA Schedule II substance, although preparations containing small amounts of dihydrocodeine can also be classified as Schedule III or Schedule V, depending on the concentration of dihydrocodeine relative to other active constituents, such as paracetamol (acetaminophen). The DEA's ACSCN for dihydrocodeine free base and all salts is 9120. The 2013 annual aggregate manufacturing quota is 250 kilos.

International treaties and the controlled-substances laws of most countries, such as the German Betäubungsmittelgesetz, regulate dihydrocodeine at the same level as codeine. Dihydrocodeine-based pharmaceuticals are especially used where chronic pain patients are able to have essentially OTC access to them provided they are registered with the provincial or national government as such a patient.

Controlled-release dihydrocodeine is a non-prescription item in some places, especially the 60 mg strength. A report by the Ivo Šandor Organisation in 2004 listed Andorra, Spain, Gibraltar and Austria as having varying degrees of access to these and other dihydrocodeine, nicocodeine and codeine products.

Chemistry

[edit]

It is available as the following salts, in approximate descending order of frequency of use: bitartrate, phosphate, hydrochloride, tartrate, hydroiodide, methyliodide, hydrobromide, sulfate, and thiocyanate. The salt to free base conversion factors are 0.67 for the bitartrate, 0.73 for the phosphate, and 0.89 for the hydrochloride.

Dihydrocodeine is the parent drug of a series of moderately strong narcotics including, among others, hydrocodone, nicocodeine, nicodicodeine, thebaine and acetyldihydrocodeine. It is an original member and chemical base of a number of similar semi-synthetic opioids such as acetyldihydrocodeine, dihydrocodeinone enol acetate, dihydroisocodeine, nicocodeine, and nicodicodeine.

Whereas converting codeine to morphine is a difficult and unrewarding task, dihydrocodeine can be converted to dihydromorphine with very high yields (over 95%). Dihydromorphine is widely used in Japan. The dihydromorphine can be quantitatively converted to hydromorphone using potassium tert butoxide.

Dihydrocodeine can be presumptively detected by the Froehde reagent.

Recreational use

[edit]

As dihydrocodeine can provide a euphoric high when taken in higher-than-therapeutic doses, it is quite commonly used recreationally. The typical recreational dose can be anything from 70 mg to 500 mg, or, in users with tolerance, even more. Potentiators and adjuvants are often included when dihydrocodeine is used in an unsupervised fashion, especially carisoprodol, glutethimide, hydroxyzine and first-generation antihistamines, both to intensify the effect and lessen side-effects such as itching.[33]

History

[edit]

Two famous users of dihydrocodeine were William S. Burroughs, who described it as "twice as strong as codeine and almost as good as heroin" and Hermann Göring, who was a known morphine addict (Hitler referred to him as the "morphinist"), consumed up to 100 tablets (3 grams) of dihydrocodeine per day and was captured by the Allies with a large quantity of the drug in a suitcase, reportedly more than 20,000 tablets[citation needed]. Another account suggest Hermann Göring was taking 20 tablets in the morning and 20 at night to ward off morphine withdrawals. Germany was experiencing a massive shortage of morphine, and as a result Göring used massive amounts of dihydrocodeine.[34] He also used morphine and oxycodone, beginning with therapeutic use of morphine after being wounded in the groin during the November 1923 Beer Hall Putsch in Munich and then used dihydrocodeine in the early 1930s for toothache.[35][36]

Society and culture

[edit]

Brand names

[edit]

Brand names for dihydrocodeine products include Drocode, Paracodeine, Parzone, Rikodeine, Trezix, Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Paramol (UK), Codidol, Dehace, DHC Continus, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine, Didrate, Dihydrin, Hydrocodin, Nadeine, Novicodin, Rapacodin, Fortuss, Remedeine, Dico, Synalgos-DC (US), and DF-118.[37]

Preparations and availability

[edit]
Package of 100 dihydrocodeine tablets

Dihydrocodeine products which can be purchased over the counter in many European and Pacific Rim countries generally contain from 2 to 20 mg of dihydrocodeine per dosing unit combined with one or more other active ingredients such as paracetamol (acetaminophen), aspirin, ibuprofen, antihistamines, decongestants, vitamins, medicinal herb preparations, and other such ingredients. In a subset of these countries and foreign possessions, 30 mg tablets and 60 mg controlled-release tablets are available over the counter and chemists may very well be able to dispense the 90 and 120 mg strengths at their discretion.

In the United States, the most common analgesic brands with dihydrocodeine are: DHC Plus (16 and 32 mg), Panlor SS (32 mg), ZerLor (32 mg), Panlor DC (16 mg) and Synalgos DC (16 mg). These combination products also include paracetamol (acetaminophen) and caffeine. Aspirin is used in the case of Synalgos DC.

Dihydrocodeine is sometimes marketed in combination preparations with paracetamol as co-dydramol (BAN) to provide greater pain relief than either agent used singly (see Synergy § Drug synergy).

In the UK and other countries, 30 mg tablets containing only dihydrocodeine as the active ingredient are available, also a 40 mg Dihydrocodeine tablet is available in the UK as DF-118 Forte.

The original dihydrocodeine product, Paracodin, is an elixir of dihydrocodeine hydroiodide also available as a Tussionex-style suspension in many European countries.

In many European countries and elsewhere in the world, the most commonly found dihydrocodeine preparations are extended-release tablets made by encasing granules of the ingredient mixture, almost always using the bitartrate salt of dihydrocodeine, of four different sizes in a wax-based binder. The usual strengths are 60, 90, and 120 mg. Common trade names for the extended-release tablets are Didor Continus, Codidol, Codi-Contin, Dicodin (made in France and the major product containing the tartrate salt), Contugesic, DHC, and DHC Continus.

Dihydrocodeine is available in Japan as tablets which contain 2.5 mg of dihydrocodeine phosphate and caffeine, the decongestant d,l-methylephedrine HCl, and the antihistamine chlorpheniramine, and packets of granules which effervesce like Alka-Seltzer with 10 mg of dihydrocodeine with lysozyme and chlorpheniramine, marketed for OTC sale as New Bron Solution-ACE. These two formulations may have once contained phenyltoloxamine citrate as the antihistamine component.

Elsewhere in the Pacific Rim, Dicogesic in analogous to Glaxo/Smith-Kline's DF-118.

The manufacturer of New Bron Solution-ACE; SS Pharmaceutical Co., Ltd, also markets an ibuprofen with dihydrocodeine product called S.Tac EVE, which also includes d,l-methylephedrine HCl, chlorpheniramine, anhydrous caffeine, and vitamins B1 and C.

The Panlor series is manufactured by Pan-American Laboratories of Covington, Louisiana, and they also market several dihydrocodeine-based prescription cough syrups in the United States.

References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Dihydrocodeine

View on Grokipedia
from Grokipedia
Dihydrocodeine is a semi-synthetic derived from through , featuring the molecular formula C₁₈H₂₃NO₃ and acting primarily as a mu- receptor to produce central analgesia. Developed in in 1908 during efforts to create more effective antitussives amid epidemics, it binds to opioid receptors in the and , suppressing , cough reflexes, and dyspnea while carrying risks of respiratory depression and dependence. Prescribed for moderate to severe , severe , and occasionally opioid management, dihydrocodeine is often formulated in immediate- or extended-release tablets, sometimes combined with or aspirin for enhanced efficacy, though such combinations heighten risks. Its pharmacokinetics involve rapid absorption, hepatic metabolism via to the active metabolite , and excretion primarily through urine, with analgesia not wholly reliant on this conversion. Common adverse effects encompass drowsiness, , , and , while higher doses amplify opioid-related toxicities like and . Despite its clinical utility, dihydrocodeine exhibits significant abuse potential akin to other s, with evidence of escalating misuse among addicts and rising overdose mortality rates, particularly when polydrug interactions occur, underscoring the need for cautious prescribing amid global opioid crises. In regulatory contexts, while approved in fixed-dose combinations like SYNALGOS-DC by the FDA, unapproved standalone formulations have faced market removals due to safety concerns.

Chemical Properties

Molecular Structure and Synthesis

Dihydrocodeine is a semi-synthetic derived from through the selective of the carbon-carbon between positions 7 and 8 in the B/C ring fusion of the morphinan core. This modification saturates the diene system present in and , resulting in a structure with formula C₁₈H₂₃NO₃ and 301.39 g/mol. First synthesized in in 1908, it retains the 3-methoxy group of while lacking the phenolic hydroxyl of , alongside the reduced ring unsaturation that distinguishes it from both parent compounds. The core morphinan scaffold consists of a fused to a ring bearing a at position 13, with dihydrocodeine's saturation at C7-C8 conferring greater rigidity compared to the unsaturated analogs. This structural alteration from minimally impacts the overall but influences and stability, with dihydrocodeine exhibiting a logP of approximately 1.2, indicative of moderate suitable for oral formulations. Industrial synthesis predominantly employs catalytic of base or salts using noble metal catalysts like or platinum oxide in acidic media, achieving yields over 90% under optimized conditions of hydrogen pressure and temperature. Microwave-assisted variants in aqueous environments further streamline the process by reducing reaction times from hours to minutes while maintaining stereochemical integrity at chiral centers. Pharmaceutical-grade production incorporates rigorous purification via or to attain purity levels exceeding 99.5%, eliminating trace or diastereomeric byproducts essential for consistent therapeutic quality. Total syntheses, such as those via sequential Claisen rearrangements followed by ring closures, demonstrate feasibility from simple aromatics but involve 16+ steps with overall yields below 30%, rendering them impractical for commercial scale.

Pharmacology

Mechanism of Action

Dihydrocodeine functions primarily as an at the μ-opioid receptors (MOR), which are G-protein-coupled receptors expressed in the , including areas involved in pain modulation and control. Binding to MOR activates inhibitory G-proteins (Gᵢ/G₀), which inhibit adenylate cyclase activity, reducing (cAMP) levels; this decreases activity, promotes potassium channel opening for neuronal hyperpolarization, and inhibits influx, ultimately suppressing the release of excitatory neurotransmitters such as and glutamate from primary afferent nociceptors and . These intracellular signaling changes diminish nociceptive signal transmission in spinal dorsal horn neurons and supraspinal sites, producing analgesia, while similar inhibition in brainstem cough centers—such as the nucleus tractus solitarius and parabrachial nucleus—raises the threshold for initiation, conferring antitussive effects. In addition to MOR, dihydrocodeine displays partial at κ-opioid receptors (KOR) and δ-opioid receptors (DOR), though with lower affinity than at MOR; this contributes to secondary effects like and potential , mediated via similar G-protein pathways but with distinct regional distributions in the . Receptor binding studies indicate dihydrocodeine's affinity for MOR (Ki ≈ 71 nM) is substantially weaker than that of (Ki ≈ 1.2 nM), correlating with its milder potency and reduced or respiratory depression risk relative to stronger full agonists. These interactions occur predominantly centrally, with limited peripheral contributions to overall efficacy, as evidenced by radioligand displacement assays in membranes.

Pharmacokinetics and Metabolism

Dihydrocodeine is rapidly absorbed after , with peak plasma concentrations typically occurring within 1 to 2 hours. Its oral averages approximately 21%, ranging from 12% to 34%, primarily limited by extensive first-pass in the liver. The drug follows a two-compartment distribution model following intravenous administration, indicating initial rapid distribution followed by slower elimination phases. is low, around 20-30%, allowing for relatively free distribution into tissues. Metabolism occurs predominantly in the liver via enzymes. The primary pathway involves O-demethylation to the dihydromorphine, catalyzed mainly by , while N-demethylation to the less active nordihydrocodeine is mediated by CYP3A4. Genetic polymorphisms in significantly influence this process; poor metabolizers exhibit impaired conversion to dihydromorphine, resulting in lower plasma levels of the and potentially reduced efficacy compared to extensive metabolizers. Pharmacokinetics remain linear across typical therapeutic doses (e.g., 60-120 mg), with no disproportionate accumulation of parent drug or metabolites upon multiple dosing. Elimination is primarily renal, with urinary excretion accounting for about 89% of the dose as unchanged drug and metabolites, showing minimal differences between metabolizer phenotypes. The terminal plasma ranges from 3.3 to 4.5 hours, with plasma clearance approximately 300 mL/min. Aging does not significantly alter these parameters in otherwise healthy individuals.

Medical Uses

Indications

Dihydrocodeine is indicated for the management of moderate to severe acute pain, including postoperative pain, trauma-related pain, and dental procedures, where non-opioid analgesics are insufficient. It is also prescribed for chronic severe pain in conditions such as cancer or non-malignant syndromes, often in modified-release formulations to provide sustained relief. As a step 2 weak on the analgesic ladder, it functions as an escalation from non-opioids like or NSAIDs, serving as an alternative to in stepwise approaches to pain control. In respiratory indications, dihydrocodeine acts as an antitussive for suppressing non-productive dry and relieving associated dyspnea, particularly in for patients with advanced disease where cough control improves comfort without addressing underlying production. It is not recommended for productive coughs, as suppression could exacerbate retention. Off-label applications include and for individuals with , historically utilized in low-threshold settings due to its availability and shorter half-life compared to . A Cochrane of randomized controlled trials found low-certainty evidence that dihydrocodeine achieves similar completion rates to during but does not demonstrate superiority in reducing illicit use or improving retention over other like . Such uses remain context-specific and are not universally approved.

Efficacy Evidence and Comparisons

Clinical trials have demonstrated that a single oral dose of dihydrocodeine 30 mg provides moderate pain relief in acute postoperative settings, with a number needed to treat (NNT) of 8.1 ( 4.1 to 540) for at least 50% pain reduction over 4 to 6 hours compared to in patients with moderate to severe pain. This indicates statistical superiority over , though the wide reflects variability and limited clinical meaningfulness, as the dose is often deemed insufficient for robust analgesia. Higher doses, such as controlled-release formulations of 90-120 mg, have shown greater reductions in pain scores at 4 hours post-administration compared to in postoperative patients. In head-to-head comparisons, dihydrocodeine exhibits analgesic potency approximately one-tenth that of morphine, positioning it as a weaker opioid similar to codeine in equianalgesic dosing (e.g., 100 mg dihydrocodeine equivalent to 10 mg morphine). Multiple-dose studies post-dental surgery found dihydrocodeine 60 mg inferior to ibuprofen for sustained analgesia beyond the first day, with ibuprofen providing superior relief on subsequent days. Long-acting dihydrocodeine has been compared to other sustained-release opioids in chronic non-cancer pain, showing no significant inter-drug differences in pain relief but highlighting its role as a step-two option on analgesic ladders, akin to codeine. For antitussive effects, dihydrocodeine reduces cough frequency in acute settings, with trials confirming efficacy comparable to other opioids like , though the latter may offer a better benefit-risk profile due to fewer adverse events. Evidence in (COPD) is limited, mirroring findings for where objective cough measures showed no superiority over ; dihydrocodeine's benefits appear short-term, with scant data supporting prolonged use amid risks of tolerance development in chronic pain or cough management. Real-world utilization remains constrained in some jurisdictions, potentially due to regulatory scrutiny on opioids, despite its established moderate efficacy profile over in targeted acute applications.

Clinical Management

Dosage and Administration

Dihydrocodeine is primarily administered orally, available as immediate-release tablets (typically 30 mg), modified-release formulations (60–120 mg), or oral solution (10 mg/5 mL). Parenteral administration via intramuscular or subcutaneous injection (as , 50 mg/mL) is available but infrequently used due to limited indications and preference for oral routes. Dosing should begin at the lowest effective amount, with based on response or symptom control, administered every 4–6 hours as needed while adhering to maximum daily limits to reduce overdose risk. For moderate pain management in adults, the standard initial dose is 30–60 mg orally every 4–6 hours, not exceeding 240 mg per 24 hours. Modified-release preparations are taken every 12 hours, starting at 60 mg, with adjustments up to 120 mg per dose if tolerated, but total daily intake must not surpass recommended maxima. Protocols from the National Institute for Health and Care Excellence () advise short-term use (typically up to 3 days for acute pain) alongside non-opioid analgesics like or ibuprofen, with regular reassessment of efficacy and sedation levels to guide continuation or discontinuation. For dry cough suppression in adults, oral solution is dosed at 10–30 mg (1–3 × 5 mL spoonfuls of 10 mg/5 mL) every 4–6 hours, limited to symptomatic relief without exceeding 120–180 mg daily depending on formulation strength. Administration can occur with or without food, though intake with meals is recommended if gastrointestinal upset occurs; patients should swallow tablets whole without crushing to maintain release profile. Efficacy monitoring involves evaluating symptom reduction within 30– post-dose, with prompts to seek medical review if inadequate response persists beyond initial trials. ![Dihydrocodeine 30 mg tablets package][float-right]

Special Populations and Contraindications

Dihydrocodeine requires dosage reduction in elderly patients due to age-related declines in hepatic and renal function, which can prolong its and heighten sensitivity to effects, increasing risks of and respiratory depression. In individuals with hepatic impairment, lower doses are recommended because the drug undergoes extensive first-pass metabolism in the liver, leading to potential accumulation and exaggerated pharmacodynamic effects. Renal impairment necessitates caution or avoidance, as active metabolites like dihydromorphine-6-glucuronide may accumulate, exacerbating toxicity despite no major pharmacokinetic differences observed solely from aging-related renal decline in some studies. Use in pediatric populations is restricted; combinations containing dihydrocodeine are not recommended for children under 12 years due to insufficient safety data and risks of life-threatening respiratory depression, akin to restrictions on similar opioids like . For children aged 1 to 11 years, dosing if used must be weight-based (0.5–1 mg/kg), but overall supports avoidance except under specialist . During , dihydrocodeine is classified as FDA Category C, indicating animal studies show adverse fetal effects but human data are limited; it should be used only if benefits outweigh risks, particularly avoiding late-term use due to neonatal syndrome risks. In poor metabolizers, who comprise about 7–10% of certain populations, formation of the dihydromorphine is impaired, potentially reducing efficacy while still exposing patients to side effects.90049-7) Contraindications include known to dihydrocodeine or opioids, severe respiratory depression, acute or severe bronchial without ventilatory support, and paralytic , as the drug's mu-opioid receptor agonism can worsen or gastrointestinal obstruction. Concurrent use with monoamine oxidase inhibitors is also contraindicated due to risks of enhanced CNS depression or excitation. Caution extends to patients with , adrenocortical insufficiency, or disease, where reduced doses mitigate heightened sensitivity.

Adverse Effects and Safety

Common Side Effects

Common side effects of dihydrocodeine, occurring in more than 1 in 100 patients but typically resolving with continued use or supportive measures, primarily affect the gastrointestinal and central nervous systems. arises due to -induced reduction in gut , with reported incidences ranging from 5% to 97% across opioid trials, though around 15% in systematic reviews of studies involving dihydrocodeine and similar agents; it is managed prophylactically with laxatives such as senna or . Nausea and vomiting, affecting up to 21% of patients in opioid cohorts, are dose-dependent and more frequent than with (e.g., sedation rates of 14% versus 5% in comparative data), often mitigated by administering the drug with food or an like metoclopramide. Drowsiness and , reported in approximately 14% of cases from post-marketing and surveillance, impair and coordination, with higher rates at elevated doses; patients are advised to avoid or operating machinery until tolerance develops. Other frequent reactions include , dry mouth, and mild , each noted in clinical observations and patient leaflets as common (≥1/100 to <1/10), though less burdensome than gastrointestinal issues. These effects are generally self-limiting and exceed placebo rates in randomized trials, underscoring dihydrocodeine's opioid profile while remaining tolerable for short-term use in most individuals.

Serious Adverse Effects

Respiratory depression represents the primary serious adverse effect associated with , a semi-synthetic opioid agonist that suppresses the respiratory drive via mu-opioid receptor activation, potentially leading to hypoxia and hypoventilation even at therapeutic doses in susceptible individuals. Clinical case reports document instances of profound respiratory depression, including loss of consciousness and myoclonic jerks, occurring in patients receiving standard doses, particularly when combined with other central nervous system depressants. Tolerance to this effect develops with chronic use, reducing risk in long-term prescribed therapy, though naive users remain vulnerable to dose-related hypoxia, with pharmacovigilance data indicating dihydrocodeine involvement in approximately 6.8% of UK opioid-related deaths from 1997 to 2007, often in polypharmacy contexts rather than monotherapy overdose. High-dose administration has been linked to seizures, though such events are infrequent and typically arise in scenarios exceeding recommended therapeutic levels, reflecting opioid-induced neuroexcitation rather than a primary epileptogenic mechanism. Anaphylaxis occurs rarely, with isolated case reports attributing severe hypersensitivity reactions, including urticaria and bronchospasm, to dihydrocodeine exposure, necessitating immediate discontinuation and supportive care. Epidemiological surveillance from pharmacovigilance databases reports serious adverse event rates around 7.5% among dihydrocodeine users in monitored cohorts, encompassing respiratory, neurological, and allergic complications, though these figures are lower than those for Schedule II opioids like morphine due to dihydrocodeine's relatively weaker potency and partial agonist profile. Monitoring for bradypnea and sedation is advised in clinical practice to mitigate these risks, particularly in elderly or comorbid patients.

Dependence, Misuse, and Overdose

Addiction Potential and Withdrawal

Dihydrocodeine, as a full μ-opioid receptor agonist, exhibits substantial abuse liability due to its activation of endogenous reward pathways, leading to euphoria and reinforcement of use behaviors. This pharmacological profile promotes tolerance through receptor downregulation and dependence via neuroadaptations in the mesolimbic dopamine system, with clinical studies indicating that approximately 5% of patients receiving opioid analgesics develop iatrogenic dependence or abuse following prolonged therapy. Dependence onset is typically slower than with short-acting opioids like , owing to dihydrocodeine's intermediate duration of action, but occurs more rapidly than with non-opioid analgesics such as NSAIDs, which lack mu-receptor affinity. Withdrawal upon discontinuation manifests as a classic opioid abstinence syndrome, characterized by flu-like symptoms including myalgia, rhinorrhea, lacrimation, diaphoresis, and yawning, alongside autonomic hyperactivity such as piloerection and nausea. Psychological symptoms encompass anxiety, irritability, insomnia, and dysphoria, with physiological signs like elevated blood pressure and tachycardia; these peak within 2-3 days for short-acting agents like dihydrocodeine and generally resolve over 7-14 days with supportive care. Management strategies emphasize gradual tapering to mitigate severity, often reducing doses by 10-25% weekly, or substitution with partial agonists like to stabilize receptor occupancy and attenuate symptoms. In opioid maintenance contexts, dihydrocodeine demonstrates efficacy comparable to methadone or buprenorphine in suppressing illicit opioid use during detoxification trials, yet carries risks of diversion and secondary dependence due to its full agonist properties and oral formulation. Low-quality evidence from randomized controlled studies underscores no superior retention or abstinence rates over alternatives, highlighting the need for supervised administration to curb misuse potential.

Patterns of Recreational Use and Abuse

Dihydrocodeine recreational use primarily involves non-medical diversion of prescription formulations in Europe, particularly the United Kingdom, where it has been obtained illicitly or through over-the-counter channels prior to stricter controls, leading to patterns of self-administration for euphoria and sedation. Misuse trends show an increase in illicit acquisition, with empirical evidence from overdose mortality indicating growing non-prescribed consumption despite its classification as a weaker opioid relative to or . In England, dihydrocodeine was implicated in 2,071 deaths from 2001 to 2020, with a statistically significant rise in cases tied to illicit sources (correlation coefficient r = 0.5, p = 0.03), representing a proxy for escalating abuse prevalence amid polydrug contexts. Common routes of recreational administration are oral, often involving crushing tablets to accelerate onset and enhance psychoactive effects, though intravenous use is less documented compared to stronger opioids. Polydrug mixing predominates, with 95.3% of fatal cases from 2001-2020 involving co-ingestants like heroin/morphine or benzodiazepines such as diazepam, amplifying respiratory depression risks and reflecting patterns where dihydrocodeine serves as an accessible opioid adjunct for intensified euphoria or withdrawal self-management. Among opioid misusers in the UK from 1997-2007, dihydrocodeine contributed to 6.8% of opiate-related deaths, with direct causation in 44% of those instances, underscoring its role in recreational polydrug scenarios beyond therapeutic intent. Drivers of abuse include its relative availability through diversion—second only to benzodiazepines in UK reports of prescribed medication misuse—and perceptions of lower potency encouraging higher dosing for desired effects, potentially masking overdose hazards. Self-medication for chronic pain, anxiety, or opioid dependence substitutes accounts for much non-medical uptake, with over-the-counter formulations linked to 42.5% of suicide-related deaths, highlighting diversion from legitimate pain relief channels. Underreporting of dihydrocodeine-specific misuse persists due to surveillance emphasis on potent synthetic opioids like fentanyl, though European data suggest it remains a niche but persistent option among 1-2% of opioid abusers favoring milder profiles for recreational or maintenance purposes, per aggregated misuse indicators.

Overdose Risks and Treatment

Overdose from typically occurs at ingested doses exceeding several hundred milligrams in opioid-naïve individuals, with acute toxicity manifesting as severe central nervous system and respiratory depression. Common symptoms include pinpoint pupils (miosis), profound drowsiness progressing to coma, bradypnea or apnea, hypotension, and hypothermia, driven by mu-opioid receptor agonism suppressing brainstem respiratory centers. Fatal respiratory arrest ensues without intervention, particularly when blood concentrations surpass therapeutic levels (e.g., >200 ng/mL plasma). Polydrug co-ingestion substantially amplifies lethality, as observed in where 95.3% of 2,071 dihydrocodeine-related deaths from 2001–2020 involved concurrent depressants such as benzodiazepines, alcohol, or , with 64.8% classified as accidental overdoses. Illicitly sourced dihydrocodeine predominated in non-suicidal fatalities, underscoring how combination use—rather than dihydrocodeine alone—multiplies hypoxic risk through synergistic suppression of ventilation and arousal. In 44% of opiate misuser deaths involving dihydrocodeine (1997–2007), it was directly causative, representing 6.8% of total fatalities, often alongside other substances. Immediate treatment centers on administration to competitively antagonize effects at mu receptors, rapidly reversing respiratory depression and restoring consciousness, as demonstrated in case reports of dihydrocodeine intoxication requiring infusion due to the drug's ~3.5–5 hour . Initial intravenous boluses of 0.4–2 mg, repeatable every 2–3 minutes, may suffice for milder cases, but continuous infusion (e.g., 50% of effective bolus dose per hour) prevents renarcotization, with supportive measures including , , and monitoring for complications like . Prompt emergency response yields high survival rates, as dihydrocodeine's lower potency relative to stronger like allows effective reversal before irreversible hypoxia, though delayed care elevates mortality. Prevention emphasizes precise dosing adherence and counseling on interaction hazards, with evidence indicating that therapeutic limits (≤240 mg/day) minimize acute toxicity when followed, though individual factors like metabolism influence susceptibility.

Controlled Substance Scheduling

Dihydrocodeine is classified under Schedule II of the (1961, as amended), which encompasses derivatives and semi-synthetic opioids with recognized medical uses but potential for abuse and dependence, subjecting them to international controls including production quotas, import/export licensing, and medical prescription requirements. Schedule II status reflects a balance between therapeutic utility for relief and cough suppression against risks of , distinguishing it from Schedule I substances lacking accepted medical value. In the United States, the (DEA) schedules dihydrocodeine as a Schedule III pursuant to the (21 U.S.C. § 812), denoting a potential for abuse less than Schedule II drugs (e.g., in higher doses or ) but greater than Schedule IV, with moderate or low risk of physical or . This placement stems from statutory criteria evaluating factors such as the drug's pharmacological profile—dihydrocodeine exhibits approximately 60-80% the potency of , yielding milder and respiratory depression—and epidemiological data indicating lower misuse rates compared to stronger opioids, while maintaining evidence-based for moderate . Debates persist on whether "weak" opioids like dihydrocodeine warrant even less stringent controls, given clinical studies showing reduced overdose lethality versus Schedule II equivalents, though regulators prioritize dependence liability evidenced by case reports of escalating tolerance. Scheduling frameworks internationally and in the U.S. emphasize medical utility against dependence risks, with dihydrocodeine's profile—supported by pharmacokinetic data of slower onset and ceiling effects on analgesia—informing its mid-tier status rather than prohibitive bans. Variations in application arise from national interpretations of convention baselines; for instance, pre-2014 pharmacy sales of low-dose dihydrocodeine combinations (e.g., ≤30 mg with ) as over-the-counter remedies highlighted assessments of negligible abuse in supervised, limited-access formats, contrasting stricter U.S. prescription mandates.

International and National Regulations

Dihydrocodeine is controlled internationally under Schedule I of the , 1961, which mandates signatory states to regulate its production, manufacture, export, import, distribution, trade, use, and possession exclusively for medical and scientific purposes while preventing diversion to illicit channels. This framework requires annual reporting of consumption statistics to the and limits availability to authorized medical channels, reflecting its classification as a semisynthetic narcotic with abuse potential akin to . In the , dihydrocodeine is designated a Class B controlled drug under the , prohibiting unauthorized possession, supply, or production with penalties up to 5 years imprisonment for possession and 14 years for supply. It is available solely by prescription, with formulations often combined with or ibuprofen subject to additional safeguards under the Misuse of Drugs Regulations 2001. Following concerns over misuse of combinations, the Medicines and Healthcare products Regulatory Agency (MHRA) issued guidance in restricting pharmacy-only sales of low-dose and dihydrocodeine products to minimize risks, effectively tightening access beyond pure prescription requirements for higher-strength preparations. This change contributed to stabilized patterns of -related misuse, though data indicate persistent involvement in overdose deaths, with dihydrocodeine implicated in increasing fatalities from 2001 to 2020 amid broader trends. In , dihydrocodeine is scheduled as Schedule 8 (controlled drug) under the Therapeutic Goods Administration's (TGA) Poisons Standard, necessitating prescriptions from authorized practitioners, secure storage, and detailed record-keeping to curb diversion. A benefit-risk by New Zealand's Medsafe, informing regional policy, affirmed dihydrocodeine's therapeutic value for and suppression despite dependence risks, leading to no immediate rescheduling; Australia's TGA echoed this in 2024 interim decisions, rejecting proposals to up-schedule low-dose preparations to avoid unintended diversion while maintaining oversight for select formulations. These measures have preserved access for legitimate use but highlighted tensions, as analogous restrictions since 2018 reduced over-the-counter availability without proportionally increasing stronger dispensing, though some patients faced barriers to non-prescription alternatives. In the United States, dihydrocodeine holds DEA Schedule II status, signifying high abuse potential with accepted medical use under severe restrictions, including triplicate prescriptions in some states and limited FDA-approved products, often in compounded forms. Its availability remains curtailed, influenced by FDA's 2013 and 2017 actions contraindicating for pediatric or due to in , with parallel warnings extending to dihydrocodeine analogs to prevent respiratory depression in vulnerable populations. By 2014, the FDA removed dozens of unapproved /dihydrocodeine products, further limiting options and bundling it with broader scrutiny. European Union regulations align with UN schedules but permit national variations in implementation; dihydrocodeine requires prescriptions across member states, with the European Medicines Agency's Pharmacovigilance Risk Assessment Committee recommending restrictions on pediatric use similar to since 2013 due to ultra-rapid metabolizer risks. For instance, mandated secure electronic prescriptions for dihydrocodeine-containing medicines starting March 1, 2025, to enhance tracking and prevent abuse, exemplifying tighter controls amid variances where some nations allow limited dispensing while others enforce specialist authorization. Overall, these regulations have demonstrably curbed misuse—evidenced by post-restriction declines in codeine-related harms applicable to dihydrocodeine—yet debates persist over excessive barriers impeding access for patients, where empirical data show no equivalent therapeutic substitutes in all cases and potential shifts to unregulated alternatives.

History

Discovery and Synthesis

Dihydrocodeine was first synthesized in 1908 in through the catalytic of , a process that reduces the between carbons 7 and 8 in the codeine's skeleton. This semi-synthetic modification aimed to produce derivatives with potentially enhanced stability and antitussive properties compared to the parent isolated from . The reaction typically employed hydrogen gas under pressure with a metal catalyst, such as or , marking an early application of techniques in chemistry amid 's leadership in pharmaceutical innovation pre-World War I. The synthesis emerged from broader efforts by German chemists and early pharmaceutical laboratories to develop superior cough suppressants, motivated by the prevalence of and other respiratory ailments requiring effective symptom control to limit disease transmission. Institutions like those affiliated with emerging firms in the conducted such work, focusing on scalable modifications without initial large-scale commercialization. Verification of the compound's structure and basic reactivity appeared in by 1911, confirming the hydrogenation product's identity through spectroscopic and derivatization studies. Early production remained limited to laboratory scales, with no immediate patents identified for the core synthesis, reflecting the era's emphasis on empirical refinement over proprietary claims for derivatives. Subsequent advancements refined yields and purity, but the 1908 method established the foundational route still referenced in modern preparations.

Development and Clinical Adoption

Following its initial synthesis and marketing in as an antitussive agent to mitigate the spread of airborne infections such as , dihydrocodeine progressed to broader evaluation for properties in the mid-20th century. Early clinical interest focused on its potential as a alternative, with animal and preliminary human studies in the 1930s and 1940s establishing its efficacy in suppressing and alleviating moderate pain, particularly amid morphine shortages during in . By the 1950s, controlled trials substantiated dihydrocodeine's superior milligram-for-milligram analgesia compared to , prompting recommendations for its expanded therapeutic trials in postoperative and settings. In the , the brand DF118—containing 30 mg dihydrocodeine —was introduced as a prescription , facilitating integration into clinical practice for moderate to severe unresponsive to non-opioids. Adoption accelerated in during this era, with formulations incorporated into cough syrups and oral tablets for respiratory conditions and , reflecting its favorable profile of lower respiratory depression risk relative to stronger opioids. Widespread use peaked in the 1970s and 1980s across the and , where annual prescriptions underscored its role as a first-line for non-cancer and persistent , often preferred over for its potency and tolerability. Regulatory shifts in the , driven by emerging evidence of misuse and overdose risks, transitioned many preparations from over-the-counter availability to prescription-only status, tempering adoption amid heightened scrutiny of analgesics.

Formulations and Society

Brand Names and Preparations

Dihydrocodeine is available in multiple commercial formulations worldwide, primarily as immediate-release oral tablets in strengths ranging from 10 mg to 60 mg dihydrocodeine tartrate, as well as oral solutions and elixirs for analgesic and antitussive use. In the United Kingdom, prominent brands include DF118 (30 mg tablets) and DF118 Forte (40 mg tablets), alongside sustained-release options like DHC Continus tablets in 60 mg, 90 mg, and 120 mg strengths for chronic pain management over 12 hours. Combination preparations are common, such as co-dydramol, which pairs dihydrocodeine tartrate (10 mg or 30 mg) with paracetamol (500 mg) in tablets, limited to a maximum of 8 tablets daily to mitigate hepatotoxicity risks from paracetamol overdose. Other mixtures include dihydrocodeine with aspirin and caffeine, as in Synalgos-DC capsules (16 mg dihydrocodeine bitartrate, 356.4 mg aspirin, 30 mg caffeine). Extended-release variants remain uncommon compared to immediate-release forms, with formulations like dihydrocodeine retard providing prolonged analgesia but requiring intact swallowing to maintain release profile. Internationally, brands such as Codidol, Contugesic, Dehace, Dicogesic, Hydrocodin, and Remedacen are marketed, often as generic tablets adhering to regional pharmacopoeial standards. All preparations must comply with quality benchmarks, including purity and identity tests outlined in the United States Pharmacopeia (USP) for dihydrocodeine bitartrate reference standards and the European Pharmacopoeia (EP) monographs.

Availability and Cultural Context

Dihydrocodeine is predominantly available by prescription in Western countries for managing moderate and persistent , reflecting stringent controls amid broader regulations. In the , it requires a prescription in forms such as tablets or liquid, with approximately 2.2 million prescriptions for dihydrocodeine tablets issued in in 2006, often positioned as a less potent alternative to stronger s like for substitution therapy. In the United States, it is similarly prescription-only under III classification, though its use remains limited compared to more common analgesics like . Supply constraints have emerged in regulated markets due to intensified oversight, contributing to intermittent shortages of medications generally, though dihydrocodeine-specific disruptions are less documented than those for injectables or higher-demand synthetics. Over-the-counter access persists in select non-Western regions, such as Japan, where dihydrocodeine is available in low-dose formulations despite its opioid nature, contrasting with the prescription dominance elsewhere. Limited evidence suggests OTC remnants in parts of Asia and Africa for codeine-related products, but dihydrocodeine specifically faces fewer such provisions, with regulatory shifts—like the UK's 2014 tightening of codeine/dihydrocodeine sales—aiming to curb misuse while preserving therapeutic access. These patterns balance legitimate pain relief needs against diversion risks, with economic factors favoring generics that keep legitimate costs low, though black market diversions command premiums akin to other opioids, often 5-10 times pharmacy prices based on regional narcotic valuations. Societal perceptions vary geographically, with the viewing dihydrocodeine as a relatively benign option in its high per-capita consumption context—leading globally for prescription s—yet linked to rising misuse deaths from 2001-2020, prompting scrutiny of its "weak" status. In the , it garners less stigma but minimal cultural footprint in narratives, playing no significant role in the crisis dominated by and prescription synthetics, where overdose statistics rarely implicate it amid over 70,000 annual deaths in 2019. Media portrayals occasionally feature it in European abuse contexts, but data underscore its peripheral involvement in North American epidemics, informing debates on access equity versus prevention without overgeneralizing risks from stronger agents.

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