Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ R) antagonism, could be an opioid adjuvant strategy. The in vitro σ R and σ R profiles of previous synthesized MOR/DOR agonists (-)-2 / -LP2 ( ), (-)-2 -LP2 ( ), and (-)-2 -LP2 ( ) were assayed. To investigate the pivotal role of -normetazocine stereochemistry, we also synthesized the (+)-2 / -LP2 ( ), (+)-2 -LP2 ( ), and (+)-2 -LP2 ( ) compounds. (-)-2 / -LP2 ( ), (-)-2 -LP2 ( ), and (-)-2 -LP2 ( ) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2 / -LP2 ( ), (+)-2 -LP2 ( ), and (+)-2 -LP2 ( ) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (-)-2 -LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2 / -LP2 ( ), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed -normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.